MX2015000739A - Novel 5-aminotetrahydroquinoline-2-carboxylic acids and use thereof. - Google Patents

Novel 5-aminotetrahydroquinoline-2-carboxylic acids and use thereof.

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Publication number
MX2015000739A
MX2015000739A MX2015000739A MX2015000739A MX2015000739A MX 2015000739 A MX2015000739 A MX 2015000739A MX 2015000739 A MX2015000739 A MX 2015000739A MX 2015000739 A MX2015000739 A MX 2015000739A MX 2015000739 A MX2015000739 A MX 2015000739A
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MX
Mexico
Prior art keywords
compound
fluorine
group
formula
methyl
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MX2015000739A
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Spanish (es)
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MX360863B (en
Inventor
Johannes-Peter Stasch
Walter Hübsch
Frank Wunder
Dieter Lang
Michael Hahn
Martina Delbeck
Joerg Keldenich
Markus Follmann
Joachim Mittendorf
Eva-Maria Becker-Pelster
Hanna Tinel
Ildiko Terebesi
René Martin
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Bayer Pharma AG
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Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of MX2015000739A publication Critical patent/MX2015000739A/en
Publication of MX360863B publication Critical patent/MX360863B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present application relates to novel 5-amino-5,6,7,8-tetrahydroquinoline-2-carboxylic acids, to processes for preparation thereof, to the use thereof for treatment and/or prevention of diseases and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of cardiovascular and cardiopulmonary disorders.

Description

NOVIDATIVE ACIDS AND THEIR USE FIELD OF THE INVENTION The present application relates to carboxylic acids to processes for their use for the treatment of prevention as well as their use for the preparation of medicaments for the treatment of prevention especially for the treatment THE PREVENTION OF CARDIOVASCULAR DISEASES AND BACKGROUND OF THE INVENTION One of the most important cell transmission systems in mammalian cells is the cyclic guanosine monophosphate together with the nitrogen monoxide that is released from the endothelium and transmits hormonal signals and forms the system. The guanylatecyclolases catalyze The biosynthesis of cGMP from the previously disclosed representatives of this family can be divided into two groups by the characteristics as well as by the type of the particulate guanylate cyclase that can be stimulated by natriuretic peptides and the soluble guanylate cyclase that can be stimulated with soluble guanilatocyclases are composed of two subunits and contain a heme per heterodimer that is a part of the center This is of central importance to the mechanism of NO can bind with the iron atom of heme and thus significantly increase the activity of the In the preparations Without carbon, carbon monoxide can also be coupled to the central iron atom. The stimulation by CO is notoriously less than stimulation through the formation of cGMP and consequent regulation of the ion channels and guanylate cyclase. a decisive role in different processes especially in the relaxation and proliferation of muscle cells platelet aggregation and adhesion and in neuronal transmission as well as in diseases that are based on a disorder of the processes before In pathophysiological conditions the system can be suppressed what for example can pr oducir hypertension hypertension activation of increased proliferation angina dysfunction of stroke and infarction insufficiency A possibility of such treatment independent of NO and which aims to influence the cGMP signaling pathway in patients is a promising approach due to the high efficiency that can The therapeutic stimulation of soluble guanylate cyclase until now has been used exclusively as nitrates whose effect is based on This is formed by bioconversion and activates the soluble guanylate cyclase by means of bonds in the central iron atom. development of tolerance is one of the decisive disadvantages of this form of treatment Evgenov et Nature Drug 5 In recent years substances directly stimulating guanylate cyclase have been identified without prior release of the indazole derivative. GCs ind ependent of but dependent on heme et From other substances were found that possess a higher potency than and do not develop a relevant inhibition of the phosphodiesterase This resulted in an identification of the pyrazole pyridine derivatives BAY BAY and BAY These compounds together with the substances recently published different and make up the new class of stimulators of the GCs et A common feature of this class of substance is a selective and independent activation of NO of the GCs containing the group the stimulators of the GCs show in combination with NO a synergistic effect on the activation of the GCs that is based on a stabilization of the complex If the heme group of the guanylate cyclase is eliminated the enzyme still demonstrates a catalytic basal activity is continuing to produce The remaining catalytic basal activity of the heme-free enzyme can not be stimulated by none of the stimulators before named et Ad ems have been identified activators of the GCs independent of the NO and the group with BAY as a prototype of this Common characteristics of these substances are that in combination with NO they only exert an additive effect on the enzymatic activation and that the activation of the oxidized or heme-free enzyme is notoriously greater in comparison with the The enzyme that contains the group hemo et Stasch et 136 Stasch et 116 spectroscopic analyzes show that BAY displaces the heme group that due to the weakening of the union of only presents a union with the It was also demonstrated that the characteristic bond motif is indispensable for both interaction of the negatively charged propionic acids of the heme group as well as for the BAY effect On this basis it is believed that the binding site of BAY 2667 to the GCs is identical to the binding site of the heme group Stasch et al. the NOX domain a prokaryotic heme binding domain with high sequence homology with respect to the have shown recently BAY joins the pocket of heme van den Akker and 285 pulmonary hypertension is a lung disease that without treatment leads to death within a few years after establishing the lung According to its in chronic pulmonary hypertension there is a pressure mean of 25 mmHg at rest or 30 mmHg under normal requirements 20 The pathophysiology of pulmonary hypertension is characterized by vasoconstriction and vessel remodeling Chronic HP produces a new primary muscularization of non-pulmonary vessels and the muscles of the lungs. already increased muscular vessels By means of this increasing obstruction of the pulmonary circulatory pathways progressively increases the requirement of the hemicadium which leads to a lower outflow of the right heart and finally produces a right hemicárdic failure Humbert et Although idiopathic hypertension is a disease Very little pulmonary hypertension HPA is quite frequent It is assumed that currently represents the third group in frequency of diseases after coronary heart disease and arterial hypertension The classification of pulmonary hypertension in different subgroups according to the respective origin is made from 2008 according to the classification Dana Point Humbert and 54 Montana and Peacock et Pulmonary diseases and their 3rd HodderArnoId Despite all the advances made in the therapy of HP so far, there are no prospects for curing this disease By means of the standard drugs available on the market analogous to antagonists of the inhibitor receptor is possible to improve the quality of the physical requirement and the prognosis of The treatment principles are applied systemically and in principle have a hemodynamic effect acting on the tone The applicability of these drugs is limited in part for the effects some of which are the forms Application The period in which the patient's clinical status can be stabilized or improved with a specific monotherapy is limited due to the development of Finally, there is an escalation of the therapy because a combination therapy is applied in which several drugs must be administered. Currently, these standard drugs are only authorized for the treatment of pulmonary arterial hypertension. In secondary forms, such therapeutic principles fail in studies given that due to a non-selective vasodium they produced a reduction of the arterial oxygen content in the cause for this is probably a negative influence on the adequacy of the in the lung in heterogeneous pulmonary diseases due to the systemic administration of non-selective vasodilators Blanco et Care Stolz and novel combination therapies are one of the most promising future treatment options for the treatment d e hypertension In this the investigation of novel pharmacological mechanisms for the treatment of HP is of special interest et Herz Expert Emerging Drugs Ito et ante Those novel therapy approaches that can be combined with the therapeutic concepts that are already in it could form the basis of a more efficient treatment so a great advantage for the selective pulmonary applicability of a novel action principle of this type could offer the possibility of only using it for the treatment of the first but also providing a first therapeutic option for patients with HP forms In an animal model for pulmonary hypertension demonstrating that the activator of GCs BAY after administration by inhalation in the form of produces a selective reduction dependent on the dose of the pressure The intravenous administration of which oxidizes the heme prosthetic group of the reduced in this model the vasodilator effect of inhaled NO while it was increased by BAY These results gave rise to the hypothesis You believe that the application of an activator of GCs by inhalation could represent a new effective treatment procedure for patients with hypertension when the reaction of these patients to ONi to PDE5 inhibitors can be diminished due to a lack of NO or an oxidation of the GCs Evgenov et Care But the same cinnakiguate in this model did not show a sufficient duration of action and in more doses produced systemic side effects. NO DESCRIPTION OF THE INVENTION It was therefore the objective of the present invention to provide novel compounds that act as the form described above as activators of the soluble guanylate cyclase and as such could be used especially for the treatment and for the prevention of diseases. Furthermore these novel compounds have to have a better selectivity of pulmonary action due to being particularly suitable for the treatment of pulmonary hypertension and its forms To this the com Novel posts should allow their combination with standard therapy but also with basic drugs in HP forms. Patent applications WO WO WO and WO disclose different aminodicarboxylic acid derivatives for the treatment of diseases. Modules of the C5a Receptor for the Treatment of Inflammatory Diseases e. WO and WO have described tetrahydronaphthalene derivatives for the treatment of diseases The WO document discloses adidas as glucagon receptor antagonists for the treatment of the diseases of the present invention. general formula in which R1 represents hydrogen or L1 represents o and A represents a group of the formula in which it indicates the respective point of attachment with the remainder of L2 represents alkanediyl of chain L3 represents one or R2 represents alkyl which may be substituted up to six times with or represents cycloalkyl that can of being mono or likewise or with a moiety selected from the group consisting of trifluoromethyl and alkyl or represents a 4 to 6 membered heterocylilyl containing one or two heteroannular or different members selected from the group consisting of S and wherein R 4 represents alkyl or alkylcarbonyl or in the case of representing an annular nitrogen atom by means of which said heterocyclyl is linked to the phenyl group is not or represents a 5-membered heteroaryl containing two or three identical or different ring heteroatoms selected from the group which consists of O and S and optionally can be fused with a ring, the heteroaryl ring and the possibly condensed phenyl ring being respectively mono or in the same or different manner with a radical selected from the group consisting of alkyl trifluoromethoxy and alkoxy or represents and R3C and R3D independently represent hydrogen or a substituent selected from the group which consists of alkyloxy difluoromethoxy and so on as their solvates and the solvates of the compounds according to the invention are the compounds of the formula and their solvates and the solvates of the compounds comprised by the formula of the formulas indicated below and their solvates and the solvates of the as the compounds comprised by the formula indicated below as embodiments and their solvates and solvates as long as the compounds comprised by the formula indicated below are no longer solvates and solvates of the preferred salts in the context of the present invention. invention are physiologically acceptable salts of the compounds according to the invention. The salts are also included which are not in themselves suitable for pharmaceutical applications but can be for the purification or storage of the compounds according to the physiologically acceptable salts. of the compounds according to the invention include addition salts n of acid of carboxylic acid acids and acids for example salts of acid acid acid acid acid toluene acid acid acid and acid The acids are physiologically acceptable salts of the compounds according to invention further include salts of bases by way of example and preferably the alkali metal salts, sodium salts and alkaline earth metal salts of calcium and and ammonium salts derived from ammonia and organic amines having 1 to 16 such atoms by way of example and preferably lysine and In the context of solvates refers to those forms of the compounds according to the invention in solid state or form a complex by coordination with molecules of the hydrates are a specific form of the solvates in which the coordination is with Preferred solvates in the context of the present invention are those depending on of the compounds according to the invention can exist in different forms is in the form of configurational isomers or eventually also as conformational isomers including those in the case of The present encompasses the enantiomers and and their respective stereoisomerically unitary constituents can be isolated of these mixtures of diastereomeric enantiomers so the chromatography processes are preferably used for in particular HPLC chromatography on an achiral phase or If the compounds according to the invention can be presented in forms the present invention includes all forms The present invention also covers all suitable isotopic variants of the compounds according to the invention A "isotopic variant" of a compound according to the invention is understood herein to mean a compound in which at least one atom within the compound according to the invention has been exchanged by another atom of the same number but with an atomic mass different from the atomic mass that usually or predominantly occurs in the Examples of isotopes that can be incorporated into a compound according to the invention are those of bromine and such as 2H 3H 129l and isotopic variants of a compound according to especially those in which one or more isotopes have been incorporated can be for the analysis of the mechanism of action or the distribution of the active ingredient in the one due to the preparation and detection relatively especially the compounds labeled with 3H or 14C isotopes are suitable for this. Further incorporation of for example can lead to particular therapeutic advantages as a consequence of greater metabolic stability of eg an extension of the half-life in the body or a reduction in the active dose these modifications of the compounds according to the invention so in some with Furthermore, it is a preferred embodiment of the present isotopic variants of the compounds according to with the invention can be prepared by methods known to those skilled in the art, for example by the methods described below and the methods described in the examples using in this respect the corresponding isotopic modifications of the respective compound reagents of the present invention it also encompasses the prodrugs of the compounds according to the term herein designates compounds which may themselves be biologically active or but are converted to an example metabolically or to compounds according to the invention during their residence time in the present invention. invention includes as prodrugs derivatives of hydrolyzable esters of the carboxylic acids according to the invention of the formula In this regard it refers to esters which can be hydrolyzed in media under the conditions of the biological assays described below and in particular in vivo by enzymatic route o giving the free carboxylic acids as the compounds of principal action. Alkyl esters in which the alkyl group can be straight chain are preferred as such or are particularly preferred in the context of the present unless otherwise specified have it. the following alkyl represents, in the context of the invention, a straight-chain or monovalent alkyl radical with 1 to 4 carbon atoms. By way of example and by way of preference, alkanediyl and alkanediyl represent, in the context of the invention, a chain alkyl radical having 1 to 6 or 3 to 5 atoms of By way of example and preferably diyl, and Alkylcarbonyl represents, in the context of the invention, a straight or branched chain alkyl radical having 1 to 4 carbon atoms which is linked by means of a carbonyl group with the rest By way of example and preferably and in the context of the invention, Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. for example and preferably and cycloalauyl represents in the context of the invention a monocyclic saturated carbocycle with 3 to 6 carbon atoms By way of example and preferably, cyclopentyl and 4 to 6-membered heterocyclyl represents, in the context of the invention, a monocyclic heterocycle saturated with a total of 4 to 6 atoms containing one or two identical or different ring heteroatoms of the group consisting of S and is attached via a carbon atom or optionally via a nitrogen atom Preferred is a 5- or 6-membered heterocyclyl containing an annular nitrogen atom and in addition another ring heteroatom of the group consisting of N u As an example is morpholinyl and Preference is given to piperazinyl and 5-membered heteroaryl represents in the context of the invention an aromatic heterocycle with a total of 5 atoms containing up to three identical or different ring heteroatoms from the group consisting of OS and bonded by means of an annular carbon atom or optionally a nitrogen atom Preferred is a 5-membered heteroaryl containing an annular nitrogen atom and further one or two other two ring heteroatoms of the group consisting of OA as an example are 1-zolyl 1 1 1 1 and 1 Preference is given to 1 1 1 1 and 1 In the context of the present invention it applies that for all residues that occur more than one the meaning is independent between When the residues are substituted in the compounds according to with the residues unless specified in can be or is preferable a substitution with one or two or three equal substituents or Especially preferred is the substitution with one or two identical substituents or A special embodiment of the present invention comprises compounds of the formula in which R1 represents as well as its solvates and the solvates of the other special embodiment of the present invention comprises compounds of the formula which R1 represents fluorine that is in position for respect to the group as well as its solvates and the solvates of the other special embodiment of the present invention comprises compounds of the formula wherein L1 represents as well as its solvates and the solvates of the other special embodiment of the present invention comprises compounds of the formula wherein L1 represents 1 as well as its solvates and the solvates of the Preferred in the context of the present invention are compounds of the formula in which R1 represents hydrogen or L1 represents or 1 and A represents a group of the formula in which indicates the point of the respective linkage with the remainder of L2 represents alkanediyl of chain L3 represents one or R2 represents alkyl which may be up to trisubstituted with or represents cyclopentyl or which may be mono or equally or with a moiety selected from the group consisting of methyl or represents a 5- or 6-membered heterocyclyl of the formula in which it denotes the respective point of attachment with the adjacent phenyl group and R4 has acetyl or represents 5-membered heteroaryl selected from the group consisting of 1 1 1 1 and the heteroaryl groups mentioned may be substituted respectively with methyl or trifluoromethyl and 1 and 1 may be fused with a ring which in turn may be substituted with trifluoromethyl or R3A represents methyl or R3B represents methoxy or R3C represents methyl or R3D represents methoxy or its solvates and solvates of the most preferred in the context of the present invention are compounds of the formula in which R1 represents hydrogen or L1 represents or 1 and A represents a group of the formula in which it indicates the respective point of attachment with the remainder of ia L2 represents alkanediyl of chain L3 represents one or R2 represents alkyl which may be trisubstituted with or represents cyclopentyl or which may be mono or in the same way or with a residue selected from the group consisting of methyl or represents a heterocyclyl of 6 members of the formula in which indicates the point of attachment with the adjacent phenyl group and R 4 represents acetyl or represents 1 1 or can be substituted with a residue selected from the group consisting of trifluoromethyl and R 3A represents methyl or R 3B represents trifluoromethyl or R3C represents methyl or R3D represents trifluoromethyl or as well as its solvates and the solvates of the Very especially preferred in the context of the present invention are compounds of the formula wherein R1 represents hydrogen or L1 represents or 1 and A represents a group of the formula in which it indicates the respective point of attachment with the remainder of L3 represents a bond or R2 represents either 1 that can be substituted with methyl or R3C represents hydrogen or and R3D represents fluorine or as well as its solvates and the solvates of the Definitions of residues indicated in particular in the respective combinations or in the preferred combinations of residues are replaced inde depending on the combinations of residues indicated in each case also by definitions of residues of others. Particularly preferred are combinations of two or several preferential areas before. The invention further provides a process for the preparation of the compounds according to the invention of the formula characterized in that a compound of the formula is reacted wherein R1 and L1 have the above-mentioned meanings and T1 and T2 are the same or different and represent alkyl in the presence of a base with a compound of the formula in which A has the meanings mentioned above and X1 represents a leaving group such by bromine triflate or a compound of the formula wherein R1 and A have the meanings mentioned above and T2 represents alkyl in the presence of a base with a compound of the formula in which L1 has the meanings before T1 represents alkyl and X2 represents a leaving group as for example tri flato o and the resulting compound in each case of the formula in which T1 and T2 have the meanings before then is transformed by hydrolysis of the groups and into the corresponding dicarboxylic acid of the formula and optionally the compounds of formula thus obtained are separated in their diastereomeric enantiomers, optionally they are transformed with The corresponding base solvents in their solvate salts are suitable as the inert solvents for the process step and suitable are, for example, ethers such as 1 or hydrocarbons such as hexane or fractions of or solvents such as dimethylsulfoxide or dinone. It is also possible to use mixtures of the solvents. Acetonitrile are suitable bases for process steps and in particular alkali carbonates such as potassium carbonate or alkali alcoholates such as sodium methanolate or sodium or potassium or sodium ethanolate or alkali hydrides such as sodium hydride or amides such as amide of lithium or amide of potassium or diisopropylamide or metallo-organic compounds as or Preference is given to using potassium carbonate or cesium as the case may be. The addition of a catalyst such as, for example, sodium iodide bromide or bromide or chloride is advantageous. The hydrolysis of the ester groups is carried out in a temperature range of a, preferably at temperatures of a. The process is carried out in accordance with the usual processes by treating the ester in inert solvents with acids or with the latter being converted to the salt. which is formed in the first instance by treatment with acid in the carboxylic acid In the case of the butyl ester the cleavage of the aster is preferentially carried out With different groups T1 and T2 the hydrolysis can possibly be carried out simultaneously in a single-vessel reaction or in two reaction steps As inert solvents are suitable for these reactions the The usual organic solvents for cleavage are preferably included. Preference is given here to alcohols such as ethers as well as other solvents such as mixtures of these. In the case of basic hydrolysis of esters, mixtures of water with dimethylformamide are preferably used. In the case of the reaction with trifluoroacetic acid, dichloromethane is preferably used and, in the case of the reaction with hydrochloric acid, dioxane is preferably used. As the bases are suitable, the inorganic bases. Especially alkali metal or alkaline earth metal hydroxides are included, such as, for example, potassium hydroxide or alkali carbonates or alkaline earth metals such as potassium carbonate or Preference is given to sodium hydroxides or As acids are generally suitable for the cleavage of acid acid, acid, acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof optionally by the addition of Preference is given to hydrochloride or In the case of butyl esters and hydrochloric acid in the case of the esters, the cleavage of the ester is generally carried out in a temperature range from a to preferably from 0 to The process steps described above can be carried out at elevated pressure or reduced in the range of 50 to 500 is usually operated in each case under pressure. The compounds of the formula in turn can be prepared by transforming by a reductive amination with one of the formula in which R1 has the meanings before in a secondary amine of the formula in which R1 has the meanings before then in the presence of a base is alkylated with a compound of the formula in which T1 and X2 have the meanings before giving a tertiary amine of the formula in which R1 and T1 have the meanings before after treatment with boron tribromide or hydrobromic acid cleaves the phenolic methyl ether group and the resulting compound of the formula a where R1 and T1 have the meanings before finally transforms by acid-catalyzed solvolysis of the nitrile group with an alcohol of the formula OH in which T 2 has the meaning above in the dicarboxylic acid ester of the formula The reaction is carried out in a usual solvent for reducing aminations which is inert under the conditions of optionally in the presence of an acid of a dehydrating agent as are part of these and alcohols as well as it is possible to use mixtures of these. Methanol is preferably used. As a catalyst, customary organic acids such as acetic acid or acid are considered as reducing agents for this amination reaction. Particularly suitable are, for example, sodium cycloborohydride cyanoborohydride borohydride or borohydride, preferably boron hydride is used. The reaction is preferably carried out in a two-in-first process over a temperature range of at the condensation of and then at a temperature of to the reduction of alkylation in the course of the process, it is carried out under analogous reaction conditions with respect to the base and as previously described in the reaction. The cleavage of the phenolic methyl ether group in the process step is carried out according to the usual procedures by treatment with boron tribromide. in dichloromethane at a temperature of ao by heating with a solution of hydrobromic acid in glacial acetic acid or water at a temperature of a Si under these reaction conditions it is also desired to effect total or partial hydrolysis of the ester group the group obtained here dicarboxylic acid of the formula in which L1 and R1 have the meanings before can by subsequent treatment with methanol or ethanol in the presence of hydrochloric acid or thionyl chloride in the dicarboxylic acid ester of the formula T2 methyl or ethyl in the compounds of the formula can be prepared by transforming the above-described compound of the formula ula in which R1 has the meanings before in the first instance using aqueous hydrobromic acid in the hydroxycarboxylic acid of the formula in which R1 has the meanings before then by acid catalysis with an alcohol of the formula OH in which T2 has the meaning before esterifying to give a compound of the formula in which R1 and T2 have the meanings before then the amine compound is transformed into a protected derivative of the formula wherein R1 and T2 have the meanings mentioned above and PG represents an amino protecting group temporary as for example below in the presence of a base is alkylated with a compound of the formula in which A and X1 have the meanings before giving a compound of the formula in which R1 and T2 have the meanings before and finally is cleaved again the temporary protective group The transformation is carried out in a manner analogous to that described above for the reaction sequence Com or protective group PG in the compound are suitable amino protecting groups, in particular those of the carbamate type, such as, for example, allyloxycarbonyl icarbonyl or The protecting group PG is selected in such a way that the conditions of its cleavage in the process step are compatible with the rest T2 used in each case The introduction and removal of the protective group are carried out according to the usual procedures Greene and Protective Groups in Organic New Preferably the group is used The alkylation in the process step is carried out under analogous reaction conditions of base and as previously described for the reaction The above-mentioned compound of the formula is novel as such and can be prepared by exchange catalyzed with the chlorine compound known in the literature the reaction scheme 1 indicated to the reaction. It is preferably carried out with zinc cyanide using as a Zador in a solvent as or in a temperature range of a The reactions described above can be carried out at elevated or reduced pressure in the range from 50 to 500. In general, the pressure is operated in each case. Separation of the compounds according to the invention in the corresponding diastereomeric enantiomers can be carried out in accordance with the invention. The separation of the stereoisomers can be carried out according to methods known to the person skilled in the art. In the context of the present invention, chromatographic methods are preferably used. in chiral separation phases or in the case of carboxylic acids as intermediates or end products alternatively separation can also be effected by diastereomeric salts using bases The compounds of the formulas and can be obtained commercially or are described as such in the literature or they can be pre stopped by the person skilled in the art in procedures known to him in analogy to those published in the Numerous detailed instructions as well as bibliographic citations for the preparation of the starting materials are also included in the experimental part in the preparation section of the compounds The preparation of the compounds according to the invention can be explained by way of example by the following Scheme 1 schemes POCI catalyst Pd also Stachel et Vanejevs et 51 Pettit et 33 Scheme 2 Cl or Scheme 3 Cl or X2 Cl The compounds according to the invention possess valuable pharmacological properties and can be used for the treatment of the prophylaxis of diseases in humans and in the context of the present term or include the la la la the rejection or the cure of a an injury or a problem of or the course or progress of these states the symptoms of these The term is understood here c omo synonymous with the term The terms or are used as synonyms in the context of the present invention and refer to the evasion or reduction of the risk of suffering or having a one an an injury or problem of or a development or advancement of these states the symptoms of these The treatment or prevention of a one an a lesion or a problem of can be partial or The compounds according to the invention act as potent stimulators of the guanylate cielase They produce a relaxation an inhibition of the thrombocytic aggregation and a reduction of the pressure as well as an increase in coronary blood flow and these effects are transmitted by means of a direct and independent activation of the heme group of soluble guanylate cyclase and by an increase in cGMP. Therefore, the compounds according to the invention have other properties with respect to to its pulmoselective action of an action its retention time in the lung its time of action after The compounds according to the invention are especially suitable for the treatment of the prevention of fibrotic diseases and The compounds according to the invention can therefore be used in medicaments for the treatment of the prevention of diseases such as hypertension, heart failure, angina stable chest or pulmonary arterial hypertension and other forms of pulmonary hypertension hypertension peripheral vascular diseases and atrial and ventricular arrhythmias and poor conduction such by atriventricular blockings of tachyarrhythmia grade fibrillation flutter flutter fibrillation tachyarrhythmia tachyarrhythmia tachycardia Torsade of atrial extrasystole and extrasystole of tachycardia dysfunction syndrome reentry of the nodule syndrome of acute coronary syndrome autoimmune cardiomyopathy of the shock cardiomyopathy such as septicemic shock shock and shock in addition to the treatment of thromboembolic diseases Olicas and such as stroke infarction hypertrophy transient attacks and cardiovascular diseases spasm of the coronary arteries and arteries such edema formation by edema edema renal edema or edema due to insufficiency circulatory circulation disorders damage of arterial thrombosis and muscle dysfunction and macrovascular dysfunction as well as to avoid restenosis for example after angioplasty therapies coronary angioplasties heart transplants and surgeries In the context of the present the concept comprises both primary and secondary subforms of this as they have been defined according to the classification of Dana Point according to their respective origin Montana and Peacock et Pulmonary diseases and their 3rd Hodder Arnold Hoeper et 54 Particularly in group 1, hypertension may include idiopathic and familial forms, or HPA also includes persistent pulmonary hypertension in newborns as well as associated hypertension that is associated with pulmonary short circuits. thermic hypertension infection by taking certain active substances and suppressant drugs with diseases with significant involvement such as disease and hemangiomatosis or with other diseases such as morbus accumulation diseases teleangiectasia myeloproliferative diseases and in group 2 of the classification Dana Point summarizes HP patients with a causative disease of the hemodiadium such as atrial conditions or Group 3 comprises forms of pulmonary hypertension that are associated with a disease due to chronic obstructive pulmonary disease interstitial lung disease pulmonary fibrosis an hypoxemia hypoventilation apnea syndrome altitude sickness malformations due to group 4 include HP patients with chronic thrombotic conditions in cases of thromboembolic obstruction of proximal and distal pulmonary arteries or in the case of non-thrombotic emboli. cause of disease bodies The less frequent forms of hypertension such as in patients with histiocytosis X or are summarized in the group In the context of the present the term also encompasses both acute and chronic forms of insufficiency and furthermore specific or related types of the such as decompensated heart failure heart failure heart failure heart failure myocardiopathy myocardiopathy cardiomyopathy heart defects heart failure associated with valve defects valve stenosis valve insufficiency valve stenosis valve insufficiency valve stenosis valve insufficiency valve stenosis valve valve heart valve defects myocardial inflammation myocarditis myocarditis myocarditis heart failure myocardiopathy thesaurism as well as diastolic heart failure and the compounds according to the invention also prophylaxis of hereditary lipid metabolism analphaipoproteinemia of obesity and hyperlipidemias can be used for the treatment and in addition syndrome compounds according to the invention can also be used for the treatment of prophylaxis of primary Raynaud's phenomenon and disorders of peripheral neuropathies and microangiopathies retinopathy Diabetic ulcers in the syndrome as well as disorders The compounds according to the invention can also be applied to avoid the damages caused by ischemia or reperfusion in organs and tissues as well as adjuvants for perfusion and conservation solutions of parts of tissues or parts of tissues of human origin or especially in surgical interventions or in the area of medicine In addition to the compounds according to the invention, prophylaxis of disorders especially of renal failure and failure is suitable for the treatment In the context of the present the t terms renal failure and renal failure comprises both acute and chronic manifestations and underlying or related kidney diseases such as hypoperfusion hypotension uropathy glomerulonephritis diseases diseases such as primary kidney disease and immunological kidney diseases such as kidney graft rejection and kidney diseases induced by substance-induced nephropathy nephropathy induced by diabetic nephropathy agents and non-hypertensive nephrosclerosis cysts and syndrome which can be characterized in a diagnostic way for example by abnormally reducing creatinine excretion of increased blood concentrations of urea in potassium form altered activity of renal enzymes such by altered urinary glutamil osmolality or volume of urine microalbuminuria lesions in the glomeruli and the hyperphosphatemia procrastination need The present invention further encompasses the use of compounds of the invention for the treatment of prophylaxis of sequelae of insufficiency by insufficiency edema example electrolyte disorders and disorders in bones and metabolism of hydrates In addition to the compounds according to the invention are suitable for treatment the prevention of diseases of the system by benign prostate syndrome benign prostatic hyperplasia benign prostate adenoma obstruction urinary bladder lower genitourinary tract syndrome neurogenic overactive bladder for example stress incontinence or overflow pain as well as erectile dysfunction and sexual dysfunction The compounds according to the invention are also suitable for the treatment of prophylaxis of lung disease disorders acute respiratory distress syndrome acute pulmonary injury antitrypsin deficiency pulmonary emphysema fibrosis example emphysema induced lung smoke and cystic fibrosis The compounds described in the present invention are also active ingredients for the fight against disease Central nervous system disorders characterized by system disorders are particularly suitable for improving learning or memory after cognitive impairments such as those that occur in particular associated with such cognitive impairment learning and memory disorders associated with the loss of memory associated with dementia traumatism accident dementia that occurs after stroke by accident head injury concentration disorders concentration disorders in children with learning disabilities and dementia disease with dementia bodies with degeneration of the frontal lobes including the supranuclear dementia paralysis disease dementia with degeneration amyolateral sclerosis sclerosis disease dementia dementia dementia due to schizophrenia with dementia or psychosis In addition they are suitable for the treatment of systemic disease prophylaxis Central nervous system such as the tension and sexual dysfunctions and sleep disorders related to and to control the pathological disorders of the intake of stimulants and substances the compounds according to the invention are also suitable for the regulation of the blood flow and in this way they are effective agents for the combat of the In addition they are suitable for the prophylaxis and the combat of sequelae of cerebral infarction such as accident ischemia and trauma The compounds according to the invention can be used in the same way to combat states of the compounds according to the invention have anti-inflammatory action and therefore can be used as anti-inflammatory for the treatment of sepsis prophylaxis multiple organ failure inflammatory disorders of chronic bowel inflammation disease of colitis diseases inflammatory diseases of the skin and eye diseases composed according to the invention are suitable for the treatment and prophylaxis of fibrotic disorders of organs, for example, those of the bone marrow and especially of and in addition to dermatological fibrosis and fibrotic disorders. In the context of the present the term especially includes the following fibrosis cirrhosis fibrosis fibrosis fibrosis renal fibrotic lesion arising from myelofibrosis and fibrotic disorders cicatrization retinopathy proliferative vitreoretinopathy and connective tissue disorders example the compounds of the invention are suitable for the control of healing eg arising from the operations of and for purposes in the case of aging and skin the basis of its profile of the compounds according to the invention are especially suitable for the treatment of prophylaxis of cardiovascular diseases and as primary and secondary forms of hypertension insufficiency angina pectoris e as well as of diseases disorders disorders insufficiency fibrot disorders icos y The present invention further provides the use of the compounds according to the invention for the treatment of the prevention of in particular of the diseases before The present invention further provides the use of the compounds according to the invention for the preparation of a medicament for the treatment the prevention of in particular of the diseases before The present invention further provides one that contains at least one of the compounds according to the treatment for the prevention of in particular of the diseases before The present invention further provides the use of The compounds according to the invention in a process for the treatment of the prevention of in particular of the diseases before The present invention further provides a method for the treatment of the prevention of in particular of the diseases above by the use of an effective amount of minimum one of the aquatic compounds The compounds according to the invention can be used alone or if necessary in combination with other principles. The present invention also relates to medicaments containing at least one of the compounds according to the invention and one or more other principles. in particular for the treatment the prevention of diseases before As suitable active ingredients for the combination are preferably indicated as organic nitrates and donors such as by way of example nitroprusside of molsidomine dinitrate mononitrate or as NO compounds that inhibit degradation cyclic guanosine monophosphate cyclic adenosine monophosphate as exemplary inhibitors of phosphodiesterases 4 especially inhibitors of PDE 4 such as roflumilasto or revamillate and inhibitors of PDE 5 such as mirodenafil or guanylatetocylase stimulators independent of but especially dependent on rlociguate as well as compounds coughs described in WO and WO WO WO and WO prostacyclin analogs and receptor agonists such as by way of example and preferably epoprostenol or receptor antagonists such as by way of example and preferably ambrisentan or compounds that inhibit human neutrophil elastase by way of example and preferably sivelestat or the compounds that inhibit the transduction cascade of in particular from the group of tyrosine inhibitors such as by way of example and preferably masitinib or compounds that inhibit rho as by way of example and preferably 23095 or agents of action as used for the treatment of chronic obstructive pulmonary disease or asthma as by way of example and preferably beta-mimetics of inhaled or systemic receptors administered or muscarinérgicos substances administered by anti-inflammatory agents as used for the treatment of a chronic obstructive pulmonary disease bronchial asthma or fibrosis as an example and preferably corticosteroids administered systemically or via azathioprine or medicines for how they are used for the treatment of neoformations of the lung or other active substances that are used for the systemic inhalative treatment of diseases such as for cystic fibrosis chronic obstructive airways diseases acute dysneic syndrome and acute lung injury obstructive sleep apnea bronchoectasia obstructive bronchiolitis and sepsis active substances that are used for the treatment of dystrophy such as for example action agents and preferably from the group of anticoagulant aggregation inhibitors or the substances the active ingredients that reduce the stress by way of example and preferably from the group of antagonists of angiotensin antagonists inhibitors of antagonists of the blockers of receptor blockers of receptor antagonist receptors s of mineral corticosteroids as well as of the active principles that modify the metabolism by way of example and preferably of the group of the agonists of the inhibitors of the synthesis of cholesterol as by way of example and preferably inhibitors of the synthesis of inhibitors of inhibitors of inhibitors of inhibitors of inhibitors of the absorption of polymeric absorbers of acids inhibitors of the reabsorption of acids and antagonists of the agents for antithrombotic action is preferably understood compounds of the group of inhibitors of the aggregation of anticoagulants or of the Substances In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with aggregation inhibitor of as by way of example and preferably ticlopidine or In a preferred embodiment of the invention, the compounds of according to the invention is administered n in combination with an inhibitor of as by way of example and preferably bivalirudin or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with an antagonist of as by way of example and preferably tirofiban or a preferred embodiment of the invention the compounds according to the invention are administered in combination with a factor inhibitor as by way of example and preferably DX DPC JTV or In a preferred embodiment of the invention the compounds according to invention are administered in combination with heparin or a low molecular weight heparin derivative. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin antagonist by way of example and preferably. by agents preferably composed of the group of anticancer antagonists angiotensin agonists inhibitors of blockers of receptor blockers of receptor antagonists of the corticosteroid receptor as well as of the drugs In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an antagonist of by way of example and preferably verapamil or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with receptor blockers as by way of example and preferably In a preferred embodiment of the invention the compounds according to the invention are administered in combination with receptor blocker as by way of example and preferably epanolol or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with angiotensin antagonists as by way of and example and preferably telmisartan or In an embodiment Preferred of the invention the compounds according to the invention are administered in combination with an ACE inhibitor such as by way of example and preferably perindopril or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with an antagonist of as by way of example and preferably ambrisentan or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with an inhibitor of as by way of example and preferably or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with a corticoid receptor antagonist as by way of example and preferably spironolactone or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with one as an example and preferentement and amiloride o By drugs that alter the fatty metabolism it is preferably understood compounds of the group of inhibitors of inhibitors of inhibitors of synthesis of cholesterol as inhibitors of the synthesis of inhibitors of inhibitors of inhibitors of absorption inhibitors of Acid Receptor-inhibiting Acid Inhibitors of Lipase Inhibitors and Acid Antagonists In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an inhibitor of as an example and preferably torcetrapib or vaccine against CETP In a preferred embodiment of the invention the compounds according to the invention are administered in combination with a receptor agonist as by way of example and preferably triiodothyronine CGS 23425 or axityroma In a preferred embodiment of the invention the compounds according to the invention are administered in combination with an inhibitor of that of the class of such as by way of example and preferably rosuvastatin or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with a inhibitor of the synthesis of as by way of example and preferably or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with an inhibitor of as by way of example and preferably eflucimibe or In a form of preferred embodiment of the invention the compounds according to the invention are administered in combination with an inhibitor of as by way of example and preferably or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with a agonist as for example and preferably pioglitazone or In a form of real Preferred embodiment of the invention the compounds according to the invention are administered in combination with an agonist of as by way of example and preferably GW 501516 or BAY In a preferred embodiment of the invention the compounds according to the invention are administered in combination with an inhibitor of the absorption of as by way of example and preferably tiqueside or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with an inhibitor of as by way of example and preferably in a preferred embodiment of the invention the compounds according to the invention are administered in combination with a polymeric adsorber of acids as by way of example and preferably colestaGel or In a preferred embodiment of the invention the compounds according to the invention are administered in combination with a resorption inhibitor of acids as for example and preferably ASBT as or in a Preferred embodiment of the invention the compounds according to the invention are administered in combination with an antagonist of as by way of example and preferably gemcabene calcium or acid The present invention further provides medicaments containing at least one compound according to the invention. General, together with one or more adjuvants not suitable for use as well as their use for the above purposes. The compounds according to the invention may have a systemic action. For this purpose they may be administered in a manner such as otically or as an implant or as For these routes the compounds according to the invention can be administered in administration forms For oral administration, suitable administration forms according to the prior art of rapid release or containing the compounds according to the invention in amorphous crystalline form are suitable. as coated tablets or not for example with re coverings resistant to gastric juices or slow dissolving or coated that control the release of the compound according to the capsules that rapidly disintegrate in the oral cavity hard gelatin capsules or aerosols o Parenteral administration can be done avoiding a step of Intraspinal absorption or using percutaneous absorption or For administration by parenteral route are suitable among others the forms of application with injectable or infusion preparations in the form of lyophilizates or powders For the other administration routes are pharmaceutical forms for inhalation inhalers in solutions or compressed aerosols for sublingual use or oral preparations or capsules aqueous suspensions mixtures suspensions transdermal therapeutic systems powder for implants or Preferably administration is intrapulmonary The compounds according to the invention can be This can be carried out in a manner known per se by mixing with adjuvants not suitable for use. Part of these adjuvants, among other examples are cellulose, polyethylene glycols, emulsifying solvents and dispersing or crosslinking agents, eg, binder sulfate, synthetic polymers and For example, it was advantageous to parenterally administer amounts of about 1, preferably about one to one, of body weight to achieve results. For administration by the dosage route, it is advantageous, for example, to provide antioxidant stabilizers, such as, for example, pigment dyes, such as oxides, and taste-improving substances. is about 100 preferably about 20 and very particularly preferably about 10 weight. For intrapulmonary administration the amount is about 50 mg per. Although it may be necessary to depart from the indicated quantities and this in relation to the weight the way of the individual reaction against the principle the form and the moment in which or the interval with which the Of that it is realized can be sufficient in some to administer less than the minimum quantity before while in other cases it is necessary to exceed the upper limit. In case of applying higher amounts it may be advisable to distribute these in several individual doses throughout. The examples of embodiment indicated below explain the invention. The invention is not limited to the percentage in the following tests and examples except indication in percentages in the parts are parts in The proportions of dilution and the data of the concentration of the solutions in each case refer to the Examples Abbreviations absolute Ac acetyl aqueous solution Boc example Bu butyl c concentration catalytic Cl chemical ionization d TLC thin layer chromatography DCI direct chemical ionization Excess of diaesteromers DMA DMF DMSO dimethylsulfoxide Ee enantiomeric excess ionization by electronic shock Ent enantiomer purity ESI electrospray ionization Et ethyl GC saturated gas chromatography h HPLC High pressure high liquid chromatography iPr concentrated isopropyl liquid chromatography coupled with mass spectroscopy Me methyl min EM mass spectroscopy NMR nuclear magnetic resonance P for Ph phenyl Pr propyl Rac racemate Rf retention index RP reverse phase at RT room temperature Rt retention time HPLC or tBu TFA trifluoroacetic acid THF tetrahydrofuran Ts toluenesulfonyl UV ultraviolet spectroscopy ratio a Procedures and Procedure 1 Type of Waters Acquity SQD UPLC Waters Acquity UPLC HSS T3 50 mm x 1 eluent 1 I water mi of formic acid to 99 eluent 1 I acetonitrile mi of formic acid at 99 min 90 A 1 min 5 A min 5 detection Procedure 2 Type of Micromass Quattro Premier with Waters UPLC Thermo Hypersilo GOLD 50 mm x 1 eluent 1 I water my acid form co to 50 eluent 1 I acetonitrile mi formic acid 50 min 97 A min 97 A min 5 A min 5 detection 210 Procedure 3 Type of Waters Acquity SQD UPLC Waters Acquity UPLC HSS T3 50 mm x 1 eluent 1 I water 25 ml formic acid to 99 eluent 1 I acetonitrile mi formic acid 99 min 90 A min 5 A min 5 detection Procedure 4 Type of Waters Acquity SQD UPLC Waters Acquity UPLC HSS T3 30 mm x 2 eluent 1 I water mi of formic acid 99 eluent 1 I acetonitrile mi formic acid 99 min 90 A min 5 A min 5 detection Method 5 Type of Thermo Trace GC Restek 15 mx 200 x constant flow with Procedure 6 Type of Waters Acquity SQD UPLC Waters Acquity UPLC HSS T3 50 mm x 1 eluent 1 I water of formic acid to 99 eluent 1 I acetonitrile mi of formic acid to 99 min 95 A min 5 A min 5 detection Starting compounds e Example 1A A solution of 250 g of yg of ammonium acetate in liters toluene it was heated to reflux for 2 hours using a The water was then absorbed in liters of acetic acid ethyl ester and 100 ml of methanol and heated to the solution. The solution was then filtered hot and cooled slowly to room temperature. The obtained crystalline precipitate was separated by filtration and dried. The g was obtained as the first batch of the product. The filtrate obtained was concentrated in vacuo to a volume of 800, seeded with a little crystalline product and Then, it was stored for 12 days. The crystalline precipitate obtained was separated by filtration and dried. Thus, another g of the product was obtained. The filtrate obtained was concentrated to dryness. The residue was dissolved in 100 ml of a mixture of acetic acid ethyl ester and methanol was applied on silica gel and purified by chromatography on silica gel ethyl ester In this way it was isolated Another g of the desired product was obtained as a solid. In total, thus, 78 g of the 1 H NMR product were obtained. Example 2A: The g and y of propionic acid methylester were heated for 1 hour under stirring. The homogenous dark solution formed was then heated. slowly After 20 min a thick mass was formed and a clear formation was produced. After another 15 min the reaction mass was thickened further while forming less After a total of 42 min the temperature was reached after others 13 min to this the reaction mass was cooled to temperature A, 200 ml of dichloromethane was added to it, it was heated in an ultrasonic bath and the crystalline residue was filtered off. This process was repeated again with another 200 ml of crystalline residues. thus obtained they were collected in 1 liters of methanol and then heated low until the solution was completely dissolved. cooled slowly to room temperature and then for 2 days it was stored in the crystalline precipitate. it was separated by filtration and dried on The g 29 of the 1H-NMR product were obtained. Example 3A Under nitrogen atmosphere g were suspended in 100 ml of acetonitrile 30 ppm and mixed with the oxychloride of the yellowish suspension after heating to and from the suspension. The yellow solution was cooled to room temperature and 150 ml of the solution was added. The solution was subsequently concentrated in a rotary evaporator to 100 ml and again mixed with 150 ml of A. The solution was concentrated to dryness in an evaporator. The orange oil obtained was mixed with 300 ml of ethyl ester. The solution was then cautiously added to 500 ml of saturated aqueous sodium hydrocarbonate solution and stirred. The layers were separated and the aqueous phase was extracted with 200 ml. The combined organic phases were washed twice with 250 ml of water and once with 100 ml of saturated sodium chloride solution were dried over sodium sulfate. filtered and concentrated to dryness. g 96 of the target compound were obtained as a lightly 1 H NMR solid. Example 4A Under a nitrogen atmosphere g g of zinc cyanide and g of 200 ml of dehydrated water anhydrous were suspended before it was heated to The reaction mixture was cooled to room temperature and filtered over celite, and the filter cake was washed with 500 ml of acetate. The organic solution obtained was stirred for 2 hours after the reaction was complete by ethyl ether. Then, it was mixed with 200 ml of saturated aqueous solution of chloride. A precipitate was formed which was separated by filtration and the phase was separated and washed three times with 200 ml of saturated sodium chloride solution dried over sodium sulfate. The obtained residue was applied to 20 g of silica gel and purified by silica gel column chromatography 80 ethyl ether in the t Then the ether was converted to ethyl ether during 30 g 66 of compound EM 172 RMN of 1H were obtained Example 5A g of carbonitrile were dissolved in 500 ml of toluene and mixed with my of yg of acid After the solution was stirred reaction for 5 hours under reflux the use of a separator of the reaction solution was evaporated to the residue was taken up in 500 ml of ethanol and under stirring was cooled to the reaction solution was then mixed in portions with g of sodium borohydride the The reaction mixture was stirred and stirred until day A. The reaction mixture was concentrated on a rotary evaporator to 100 ml of and mixed with 300 ml of water and 300 ml of acetate. The phases were separated and the aqueous phase was extracted twice. with 150 ml of acetate The combined organic phases were washed twice with 250 ml of saturated sodium chloride solution, dried over sulfate, filtered and concentrated to a volume of 150 ml in an evaporator. thus obtained it was applied on 50 g of silica gel and purified by silica gel column chromatography 80 75 ethyl ether in the course of 45 g of the compound 1 H NMR compound were obtained. Example 6A ethyl pentanoate A solution of 300 ml of dry acetonitrile was mixed with my g of potassium iodide and g of anhydrous sodium carbonate and heated for 4 days. The mixture was then concentrated to a volume of 50 ml in an evaporator. It was taken up in 250 ml of ethyl acetate and 400 ml of saturated aqueous sodium chloride solution and then the phase was separated The aqueous phase was extracted twice with respectively 150 ml of acetate The combined organic phases were dried over sulphate were filtered The residue obtained was applied on 25 g of silica gel and was purified by silica gel column chromatography 80 60 ethyl ether in the course of 30 hours. had content 52 of the target compound as 1 H NMR color oil partially covered by the signal of Example 7A of ethyl Under a nitrogen atmosphere, g of ethyl were suspended in 175 ml of hydrobromic acid. The syrup-like solution was then heated to and agitated for 5 hours at this. The yellow reaction solution was then added at room temperature and concentrated to a The residue obtained was then mixed with 350 ml of anhydrous ethanol and 25 ml of a 4N solution of hydrochloric acid in dioxane and stirred until the next day. The reaction mixture was then concentrated on a rotary evaporator at 50 ml. 550 ml of saturated aqueous sodium hydrogencarbonate solution and extracted three times with respectively 150 ml of acetate The combined organic phases were dried over sulphate and filtered, and the residue obtained in color was dissolved in 100 ml of ethyl acetate. it was mixed with 65 g of silica gel and again evaporated to. The residue was then purified by gel column chromatography. Metallic silica gel 58 x 8 1600 ml of petroleum acetate gel 1 after 3 liters 1 after liters G 38 of the objective compound was obtained as EM oil 468 1N NMR partially covered by the signal of Example 8A Carboxylic acid. The reaction solution was cooled to room temperature and diluted with water and saturated sodium bicarbonate solution was adjusted to a pH value. The crystals formed were separated by a mixture of 100 ml of hydrobromic acid and stirred for 5 hours at room temperature. filtration were washed with water and dried in. g 98 of compound 313 were obtained. Ethyl example 9A g of acid were mixed with 645 ml of anhydrous ethanol and 52 ml of a 4N solution of hydrochloric acid in dioxane and stirred to the bottom. After the reaction solution was cooled to room temperature, it was first mixed with ethyl acetate and then slowly with saturated aqueous hydrogen carbonate solution. The phase was separated, dried over sulfate, filtered and concentrated to give 85 g of the compound Rt 341 1H-NMR CDC Example 10A of ethyl G of ethyl was dissolved in 530 ml of dichloromethane and stirred under stirring at 0 A Then a solution of g of dicarbonate in 30 ml of dichloromethane was slowly added dropwise and the reaction mixture was stirred overnight at the temperature the reaction solution was concentrated to dryness and the residue was stirred by mixing with after filtration the filter cake was washed several times with ethanol and finally dried on g G 88 of compound Rt 441 1H NMR CDC partially covered by the signal of Example 11A were obtained. 50 g of in methanol methoxyethanol were mixed under stirring with g. of hydrogencarbonate of A were added dropwise to the solution g of dissolved in 250 ml of in the course of 15 During this time an increase in the reaction temperature was observed from temper After 4 hours, 1 liter of water and 10 ml of hydrochloric acid were added to the reaction mixture. The crystals formed were separated by filtration and dried. 116 g of the compound were obtained, which was further processed without another Rt 276 Example 12A 116 g 406 g of 700 ml of 1 were stirred under stirring with 5 g of acid A, the reaction solution was heated to the bath and stirred for 3 hours at this temperature in a separator of the reaction solution was cooled to The temperature was mixed with 200 ml of hexane and the mixture was continued stirring. The precipitated solid was separated by washing with hexane and dried. There were obtained 56 g of the compound Rt 258 1H NMR CDC Example 13A of paraformaldehyde and g of zinc chloride in 200 ml of Then, under vigorous stirring, gaseous hydrochloric acid was passed through the mixture for 30 min. After the end of the reaction mixture, the gas was continued. the next day at room temperature The reaction solution was mixed with the organic phase and separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sulfate, filtered and concentrated to dryness in an evaporator. The obtained residue was purified by HPLC. During the concentration, the product produced the partial hydrolysis of the product in the compound. the mixture of the obtained product was absorbed under stirring in 100 ml of THF and mixed with 500 mg zinc chloride and then 2 ml of chloride. This mixture was then stirred for 1 hour at a temperature after the addition of water and ethyl acetate to the mixture. The solution was separated and the dried phase was filtered over sodium sulfate, filtered and concentrated. G 56 of the compound Rt 266 1 H NMR partially covered by the signal of Example 14A was obtained. Under argon atmosphere, 2 g of the preparation was dissolved, see FIG. WO patent application 8 steps in THF 40 and successively were mixed with triphenylphosphine g and tetrabromide g of the reaction mixture After stirring the phase, the mixture was dried over a sulphate and filtered. g 83 of the compound Rt 422 1H NMR CDC Example 15A of ethyl Under argon atmosphere 500 mg of 246 mg of as well as 295 mg of potassium carbonate in 5 ml of DMF were heated and stirred 6 hours to this After Water and ethyl acetate were added to the reaction mixture and then the organic phases were washed twice with water and once with saturated sodium chloride solution and then concentrated to obtain 760 mg content 94 of compound Rt 663 Analogously to example 15A, the following compounds were prepared from the indicated starting materials Example 18A of ethyl 5 g of g of yg of potassium carbonate in 50 ml of acetonitrile They were heated and stirred until the next day after being filtered. The mixture of the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness in an evaporator. The obtained residue was purified by chromatography on silica gel. ethyl G 87 of compound Rt 662 1 H NMR were obtained. Analogously to example 18A, the following compounds were prepared from the indicated starting materials Example 22A of ethyl 250 mg of ethyl 277 mg of and 118 mg of potassium carbonate in 10 g. ml of acetonitrile were heated to and stirred 4 h. After the mixture was filtered the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness in an evaporator. The residue obtained was purified by chromatography on silica gel of ethyl The product thus obtained was again purified by preparative HPLC 182 mg 45 of compound Rt were obtained Analogously to Example 18A the following compounds were also prepared from the starting materials respectively Example 25A v Example of ethyl enantiomer 1 and g were separated from the racemic ethyl carboxylate by supercritical liquid chromatography in chiral phase in the Daicel Chiracel enantiomers 5 250 mm x 20 125 detection dioxide 210 Example 25A ethyl enantiomer 2864 mg Rt chemical purity ee Chiralpak 5 250 mm x 4 detection dioxide 210 c Rt 662 1 H NMR Example 26A of ethyl 2359 mg Rt chemical purity e Chiralpak 5 250 mm x 4 dioxide detection 210 c Rt 1662 NMR of 1H Example 27A of ethyl dihydrochloride enantiomer 581 mg of ethyl carboxylate were mixed with 5 ml of a 4 N solution of hydrochloric acid in dioxane and stirred 4 h at room temperature The reaction solution was subsequently concentrated to dryness and the residue was dried until the next day at high 564 mg 100 of the objective product were obtained as solid color Rt 562 NMR of 1 H Example 28A of ethyl enantiomeric dihydrochloride 620 mg of ethyl carboxylate were mixed with me of a 4 N solution of hydrochloric acid in dioxane and stirred 4 h at room temperature The reaction solution was subsequently concentrated to dryness and the residue was dried until the next day at high 604 mg 100 of the objective product was obtained as a solid color Rt 562 Analogously to examples 27A and 28A, the following ethyl examples 35A were prepared. A solution of 543 mg of ethyl dihydrochloride in 10 ml of dry acetonitrile was mixed with my of 14 mg of potassium iodide and 372 mg of carbonate. Anhydrous sodium was added and the mixture was heated to reflux until the next day. Then, another ethyl ester was added and the mixture was stirred for 8 hours. Then my ethyl ester was added again, as well as 14 mg of potassium iodide and until the day The following was continued heating to After a new addition of my of ethyl bromopentanoate was stirred again for 8 hours a Finally 14 mg of iodide of potassium and the mixture was continued heating until the next day to the preparation after the filter cake was washed with acetonitrile and the filtrate was concentrated to The residue obtained was purified by chromatography on ethyl silica gel 396 mg 67 of the compound were obtained Reference medium as oil Rt 1 690 1 H NMR partially covered by the c-signal Example 36A of ethyl enantiomer A solution of 564 mg of ethyl dihydrochloride example in 10 ml of dry acetonitrile was mixed with my of 15 mg of potassium iodide as well as 283 mg of anhydrous sodium carbonate and it was heated to reflux until the day. Then, another one of ethyl was added and the mixture was continued stirring for 8 hours. Then my ethyl was added again as well as 14 mg of iodide. of potassium and heating was continued until the next day after a new addition of my ethyl bromopentanoate was stirred again for 8 hours to finally they added again 14 mg of potassium iodide and the mixture was continued heating until the next day at the preparation after the filter cake was washed with acetonitrile and the filtrate was concentrated to The obtained residue was purified by chromatography on ethyl silica gel 320 mg 52 of the reference compound were obtained as an RH 1 690 1 H NMR oil partially covered by the c-signal. Analogously to examples 35A and 36A, the following were prepared Example 43A of ethyl A solution of 210 mg of ethyl dihydrochloride in 4%. My dry-acetonitrile was mixed with 129 mg of methyl and 91 mg of anhydrous sodium carbonate and heated to reflux for 4 hours. Then, another ml of methyl was added and the mixture was stirred for 4 hours. again my methyl ester and the mixture was then heated to reflux until the day. Then again my as well as 100 mg of sodium carbonate were added. The mixture was stirred for a further 2 hours and the mixture was further stirred for 2 days. The residue was purified by HPLC. 38 mg content 14 of the compound were obtained. reference as Rt 649 oil Example 44A Example 45A ethyl enantiomer 1 ypg racemic ethyl carboxylate by preparative HPLC in chiral phase in the chiral phase enantiomers of silica gel on the basis of the selector on silica gel SH 10 250 mm x 20 acetate of detection 270 Example 44A 318 mg Rt chemical purity of the chiral phase of silica gel on the basis of the selector in silica gel SH 5 250 mm x 4 detection acetate 260 Example 45A 316 mg Rt chemical purity in the chiral phase of gel of silica on the basis of the selector in silica gel SH 5 250 mm x 4 detection acetate 260 Example 46A v Example 47A of ethyl enantiomer 1 and 69 mg of racemic ethyl were separated by HPLC preparation in chiral phase in Daicel Chiralcel enantiomers 5 250 mm x 20 diethylamine 15 Detection 220 Example 46A 28 mg Rt Chemical purity eic Daicel Chiralcel 5 250 mm x ethanol hexane diethylamine 1 detection 220 Rt 737 c Example 47A enantiomer 29 mg Rt chemical purity e Daicel Chiralcel 5 250 mm x ethanol hexane diethylamine 1 detection 220 Rt 737 c Example 48A v Example 49A of ethyl enantiomer 1 and 67 mg of racemic ethyl were separated by preparative HPLC in chiral phase in the Daicel Chiralcel enantiomers 5 250 mm x 20 detection 220 Example 48A 14 mg Rt chemical purity eic Daicel Chiralcel 5 250 mm x ethanol hexane diethylamine 1 detection 220 Rt 615 Example 49A enantiomer 10 mg Rt chemical purity eic Daicel Chiralcel 5 250 mm x ethanol hexane diethylamine 1 detection 220 Rt 615 Example 50A Example 51 A ethyl enantiomer 1 and 760 mg of racemic ethyl were separated by Preparative HPLC in chiral phase in the Daicel Chiralpak enantiomers 5 250 mm x 20 propanol 20 detection 210 Example 50A enantiomer 261 mg Rt chemical purity ee Daicel Chira lpak 5 250 mm x 1 detection 230 Rt 1 663 Example 51A 276 mg Rt chemical purity eic Daicel Chiralpak 5 250 mm x 1 detection 230 nm Rt 663 Example 52A Example 53A of ethyl enantiomer 1 y 603 mg of ethyl racemic were separated by HPLC preparative chiral phase in the Daicel Chiralpak enantiomers 5 250 mm x 20 20 detection 230 Example 52A enantiomer 70 mg Rt chemical purity eic Daicel Chiralpak 5 250 mm x propanol 1 detection 230 Rt 681 Example 53A 72 mg Rt chemical purity eic Daicel Chiralpak 5 250 mm x propanol 1 detection 230 Rt 681 Example 54A v Example 55A of ethyl enantiomer 1 and 642 mg of racemic ethyl carboxylate were separated by preparative HPLC in chiral phase in Daicel Chiralpak enantiomers 5 250 mm x 20 detection 220 Example 54A enantiomer 161 mg Rt chemical purity ee Daicel Chiralpak 5 250 mm x 1 detection 220 Rt 703 Example 55A enantiomer 168 mg Rt chemical purity eic Daicel Chiralpak 5 250 mm x propanol 1 detection 220 Rt 1 703 Ana The following compound was prepared from the starting materials analogously to example 11A. Analogously to example 12A, the following compound was prepared from the starting material. Analogously to example 18A, the following compound was prepared from the starting products Example 59A v Example 60A of ethyl enantiomer 1 yi 494 mg of racemic ethyl carboxylate were separated by supercritical liquid chromatography in chiral phase in the Daicel Chiracel enantiomers 5 250 mm x 20 100 detection dioxide 210 Example 59A 247 mg Rt chemical purity e Chiralpak 5 250 mm x dioxide of detection 210 Rt Example 60A enantiomer 213 mg Rt chemical purity e Chiralpak 5 250 mm x 3 detection dioxide 210 Rt Example 61A ethyl enantiomer 247 mg of ethyl example were mixed with 10 ml of a 4 N solution of hydrochloric acid in dioxane and stirred 4 h at room temperature. The reaction solution was subsequently concentrated to dryness and the residue dried until the next day at high 210 mg of the reference compound were obtained as hydrochloride in the form of a solid This was absorbed in 5 ml of it was mixed with my triethylamine and stirred one hour at temperature The mixture was subsequently mixed with water and acetate The aqueous phase was extracted twice with ethyl acetate and then the combined organic phases were dried over sulfate, filtered and then concentrated. 149 mg 72 of compound Rt NMR of 1H DMSO was obtained Analogously to example 61 The following Example 63A of ethyl enantiomer was prepared A solution of 149 mg of ethyl Example 61 in 10 ml of dry acetonitrile was mixed with 112 mg of methyl and 41 mg of anhydrous sodium carbonate and heated to reflux until the day Then another 112 mg of methyl were added and the mixture was again heated to reflux until the day. The preparation was then concentrated to the residue was absorbed in water and acetate. The organic phase was concentrated to dryness and the residue obtained it was purified by HPLC 72 mg 38 of the Rt compound were obtained Analogously to example 63A the following Example 65A of ethyl enantiomer Se was prepared and g of ethyl dihydrochloride were dissolved in 50 ml of mixed with my triethylamine and stirred for 1 h The mixture was subsequently mixed with water and ethyl acetate and the layers were separated. The aqueous phase was extracted twice with acetate, then the combined organic phases were dried over sulphate and filtered and concentrated. 562 1 H NMR Analogously to Example 65A, the following Example 69A of ethyl enantiomer was prepared. 10 g of example ethyl carboxylate were dissolved in 500 ml of ethanol and mixed with g of ammonium formate as well as 161 mg of 10 of palladium on carbon. Thereafter, the reaction mixture was heated to and stirred until the next day. After the mixture was cooled to room temperature, it was again mixed with water. 100 mg of the palladium catalyst and stirred another 6 h. The reaction mixture was then cooled again to a temperature filtered and the filtrate was evaporated. The residue obtained was purified by chromatography on ethyl silica gel. 441 An alternative synthetic route to Example 69A has been indicated in relation to the description of Example 147A Analogously to Example 11A the following compounds were prepared from the starting products Analogously to Example 12A the following compounds were prepared from the starting product Example 74A of ethyl enantiomer A suspension of ethylglute g of yg of potassium carbonate in 1420 ml of acetonitrile was heated to and stirred until the next day after it was filtered. The filter cake mixture was washed several times. times with acetonitrile and the combined filtrates were concentrated to dryness in an evaporator. The residue obtained was purified by evaporation. romatographically on silica gel ethyl ether 79 g 96 of compound Rt 709 1 H NMR were obtained An alternative synthetic route to Example 74A has been indicated in relation to the description of example 148A Analogously to the example described above 74A the following were prepared Compounds from the indicated starting materials Example 80A of ethyl dihydrochloride enantiomer 79 g of example ethyl carboxylate were mixed with 557 ml of a 4 N solution of hydrochloric acid in diluted with another 389 ml of and stirred until the next day after temperature The reaction solution was subsequently concentrated to dryness and the residue was dried overnight at high. 78 g of the product Rt were obtained. Analogously to Example 80A, the following were prepared Example 86A of ethyl enantiomer 78 g of ethyl carboxylate were suspended Example dihydrochloride in 1200 ml of was mixed with 47 ml of triethylamine and stirred for 1 h at room temperature. After this, the precipitated crystals of triethylammonium chloride were filtered off and subsequently washed with water. The obtained filtrate was evaporated and the residue was dissolved in ethyl acetate, washed twice with 10 aqueous solution of chloride, dried over sulphate and filtered. it was evaporated again to 69 g of the compound Rt NMR of 1H were obtained. Analogously to example 86A the following were prepared Example 92A of ethyl enantiomer A suspension of 69 g of ethyl carboxylate, example 129 g of methyl and g of anhydrous sodium carbonate in 1500 of dry acetonitrile were stirred at a bath temperature of up to the day. Then, additional g of methyl as well as powdered potassium carbonate were added and the mixture was again heated to reflux for 48 hours. After cooling the reaction mixture was stirred. the inorganic salts were filtered off and the obtained filtrate was evaporated. The resulting residue was absorbed in the sewage acetate. or twice with 10 aqueous solution of chloride dried over sulfate was filtered The residue obtained was chromatographically purified on silica gel, ethyl ether. 42 g 49 of the Rt NMR compound of 1H were obtained Analogously to Example 92A, the following were prepared Analogously to Examples 35A and 36A, the following were prepared Example 103A Carbonitrile G g of Reg and g of acid were dissolved in 511 ml of toluene and the solution was stirred overnight at reflux using a separator. Then 200 ml of toluene was distilled off and after cooling was replaced by toluene After the reaction solution was evaporated to dryness and the resulting residue was taken up in 511 ml of anhydrous ethanol and 511 ml of THF. The solution was mixed under stirring at a temperature of in portions with g of sodium borohydride the reaction mixture form the reaction solution was continued to stir at the same temperature until day. The reaction mixture was then mixed cautiously The combined organic phases were dried over sodium sulfate and filtered, and then the residue was concentrated. The residue thus obtained was purified by column chromatography on ethyl silica gel. G46 of compound Rt 326 1 H NMR was obtained. Example 104A Racemic carboxylic acid G was suspended in 360 ml of hydrobromic acid in and was first stirred for 12 h at room temperature then cooled to room temperature and allowed to stand overnight Following this, the reaction solution was diluted with 400 ml of diluted water and adjusted with a saturated sodium hydrogencarbonate solution to a pH value. The crystals formed were filtered off, washed with water and dried under vacuum at 50 ° C. obtained 59 g 80 of compound Rt 331 Example 105A ethyl carboxylate G racemic acid was mixed with 40 ml of anhydrous ethanol and 4 ml of A 4 N solution of hydrochloric acid in dioxane was added and stirred overnight. The reaction solution was then cooled to room temperature and mixed first with ethyl acetate and then slowly with saturated aqueous hydrogen carbonate solution. The mixture was dried over sulfate and filtered to give 80 g of compound Rt 359 1 H NMR. Example 106A of ethyl. g of ethyl were dissolved in 30 ml of dichloromethane and, under stirring, cooled to 0, then slowly added dropwise. dropwise a solution of g of butyldicarbonate in 10 ml of dichloromethane and the reaction mixture was stirred overnight at the temperature the reaction solution was concentrated to dryness and the residue was mixed with stirring. After the filter cake was washed several times with diethyl ether and finally dried on. G 87 of the compound Rt 459 1 H NMR partially covered by the 1 1 1 signal were obtained. Example 107 A of ethyl. G of g of yg of potassium carbonate in 120 ml of acetonitrile were added to and stirred until the next day after it was filtered. The mixture of the filter cake was washed several times with acetonitrile and the combined filtrates. were concentrated to dryness in an evaporator. The residue obtained was purified by chromatography on ethyl silica gel. 85 g of compound Rt were obtained. Example v Example of ethyl enantiomer 1 and g were separated from racemic ethyl carboxylate by supercritical liquid chromatography in chiral phase in the enantiomers Daicel Chiracel 5 250 mm x 20 dioxide 100 detection 220 Example 108A 1020 mg Rt chemical purity ee Chiralpak 5 250 mm x 3 detection dioxide 210 Rt Example 109A 1040 mg Rt chemical purity ee Chiralpak 5 250 mm x 3 detection dioxide 210 Rt 1 H NMR partially covered by the signal Analogously to Example 107A, the following Example v Example 112A of ethyl 1 was prepared and separated on g of the racemic ethyl carboxylate by chiral phase supercritical liquid chromatography on the enantiomers Daicel Chiracel 20 250 mm x 30 dioxide 175 detection 210 Example 111A enantiomer 1130 mg Rt chemical purity ee Chiralpak 5 250 mm x 3 detection dioxide 210 Example 112A 1170 mg Rt chemical purity e Chiralpak 5 250 mm x 3 detection dioxide 210 Rt Example 113A of ethyl enantiomeric dihydrochloride 1025 mg of ethyl ester were mixed with a 4N solution of hydrochloric acid in dioxane with me and stirred for 2 h at room temperature. The precipitated solid was separated by washing several times with diethylether and then drying until dry. the following day to high vacuum a 980 mg 99 of the Rt product were obtained Analogously to example 113A the following example 117A of ethyl enantiomer was prepared. 980 mg of ethyl carboxylate dihydrochloride were suspended in 20 ml of mixed with my triethylamine and The mixture was stirred for 1 h at room temperature. The reaction solution was then mixed with ethyl acetate and the phases were separated and the organic phase was separated. The organic phase was extracted once more with ethyl acetate. The combined organic phases were washed with dried over sulphate, filtered and then evaporated to give 760 mg 87 of the Rt NMR compound of 1H. Analogously to example 117A, the following was prepared analogously to the Examples 35A and 36A were prepared as follows Example 121A of ethyl enantiomer A suspension of 375 mg of ethyl carboxylate, Example 272 mg of methyl and 99 mg of anhydrous sodium carbonate in 10 ml of dry acetonitrile were stirred at a bath temperature of until the next, another 272 mg of methyl as well as 99 mg of sodium carbonate were added and the mixture was again heated to reflux until the day. Then 272 mg of methyl and 99 mg of sodium carbonate were added again and the The mixture was again heated to reflux until the day after cooling the mixture, ethyl acetate was added and the organic phase was separated and the aqueous phase was extracted three times. The combined organic phases were dried over sulphate, filtered and evaporated. The residue obtained was purified by chromatography on silica gel ethyl ether 324 mg 68 of the Rt NMR compound of 1H DMSO were obtained Analogously to the example 121A the following Example 123A of ethyl was prepared. A solution of 740 mg of ethyl carboxylate dihydrochloride example in 20 ml of dry acetonitrile was mixed with 685 mg of methyl and 188 mg of anhydrous sodium carbonate and heated to reflux until the day Then, another 342 mg of methyl were added and the mixture was continued stirring until the following day. This process was repeated twice more in the days. Then, 342 mg of methyl and 188 mg of anhydrous sodium carbonate were added again. the mixture was stirred again until the next day at the reaction solution was finally mixed once more with 342 mg of of it was heated to reflux until the day if The residue was then taken up in ethyl acetate and the mixture was filtered off. The residue was filtered off and evaporated. a The residue obtained was purified by chromatography on ethyl silica gel 588 mg 63 of the Rt NMR compound were obtained Analogously to Example 123A the following methyl example 125A was prepared. g of yg methyl bromide was dissolved in 250 ml. they were cooled to 0 and mixed in portions with g of methanolate. Then, the reaction mixture was heated slowly to room temperature and stirred until the next day. After the reaction solution was cooled again to 0, it was mixed in portions with water. Another g of sodium methanolate and after heating to room temperature was continued stirring again until the day. The precipitated solid was separated by was washed with water. Ethanol and dried until the next day after drying in. G g of the compound was obtained The filtrate was evaporated to dryness and the residue obtained was purified by chromatography on ethyl silica gel. Other g 52 of the compound of Rt 257 Rt 257 were thus obtained Example 126A of methyl 44 g of methyl in 500 ml of THF were mixed with 2 g of palladium to 10 on charcoal and was stirred overnight at room temperature under a pressurized hydrogen atmosphere. Then 1 g of 10-palladium-on-charcoal was added again and the mixture was stirred again until the next day at room temperature under an ambient atmosphere. Pressurized hydrogen The reaction mixture was then filtered and the resulting filtrate was concentrated to 35 g of the compound of Rt 259 were obtained. Example 127A To a solution of g of methyl in 500 ml of dry THF were slowly added dropwise at reflux 45 ml of an M solution of lithium aluminum hydride in After the addition was complete, stirring the reaction mixture was continued for one hour at A the mixture was cooled reaction to 0 and mixed slowly and cautiously with 500 ml of 1 M hydrochloric acid cooled with 750 ml of acetate were added, the aqueous phase was separated and the organic phase was washed successively once with 1 M hydrochloric acid and once with saturated sodium chloride solution. The organic phase was then dried over sulfate and filtered and concentrated. The g of the compound of Rt 213 NMR of Example 128A was obtained. To a solution of g of in 400 ml of dichloromethane were slowly added dropwise. After the reaction mixture was heated to room temperature and stirring was continued for two hours, the reaction mixture was again cooled to 0 and mixed slowly. cautiously under heavy stirring with 200 ml of saturated aqueous solution of hydrogencarbonate from A the solution was mixed with small portions of solid sodium hydrogencarbonate until it was adjusted Afterwards, the phases were separated and the organic phase was dried over sulphate, filtered and concentrated to give 84 g of 1 H NMR compound were obtained. Example 129A of ethyl G g of yg of carbonate was heated potassium in 200 ml of acetonitrile a and stirred until the next day after it was filtered. The mixture of the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness in an evaporator. The obtained residue was purified by chromatography on ethyl silica gel G 82 of compound Rt 653 Example 130A v Example 131A of ethyl enantiomer 1 and g were separated from racemic ethyl by supercritical liquid chromatography in chiral phase in Chiracel enantiomers 20 250 mm x 30 carbon dioxide ethanol 185 detection 210 Example 130A 3240 mg Rt chemical purity ee Chiralpak 5 250 mm x 3 detection dioxide 210 Rt 653 Example 131 A enantiomer 3180 mg Rt purity Chemistry ee Chiralpak 5 250 mm x 3 detection dioxide 210 Rt 653 Example 132A of ethyl dihydrochloride enantiomer 3180 mg of ethyl example 131 were mixed with 12 ml of a 4 N solution of hydrochloric acid in dioxane and stirred for 2 h at room temperature. The mixture was then concentrated to dryness. 3290 mg of the product was obtained which was further processed without further characterization. Analogously to Example 132A, the following Example 134A of ethyl enantiomer was prepared. 3290 mg of ethyl dihydrochloride were suspended in 50 ml of the mixture. ml of triethylamine and stirred for one hour at room temperature. The reaction solution was then mixed with ethyl acetate and the phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed again with drying. sulfate were filtered and then evaporated to 2150 mg 70 of compound Rt 553 1 H NMR were obtained Analogously To Example 134A the following Example 136A of ethyl enantiomer was prepared A solution of 1980 mg of ethyl Example in 30 ml of dry acetonitrile was mixed with 3118 mg of methyl and 570 mg of anhydrous sodium carbonate and heated to reflux until day. Then another 379 mg of methyl were added and the mixture was stirred again until the day After 379 mg of the mixture were added again after stirring for three days under reflux and finally cooled to room temperature. The preparation of the filter cake was washed with acetonitrile and the filtrate was concentrated to the residue obtained by chromatography. in ethyl silica gel 715 mg content 67 of the compound of Rt 715 c were obtained. Analogously to example 136A, the following example was prepared from ethyl Example 138A. 10 g of ethyl g of yg of potassium carbonate in 240 ml of acetonitrile a were heated. They were stirred until the next day after they were filtered. The mixture of the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated as Evaporator Evacuation The residue obtained was purified by chromatography on ethyl silica gel. 96 g of compound Rt 671 were obtained. Example 139A Example 140A of ethyl enantiomer 1 and g were separated from racemic ethyl carboxylate by chiral phase supercritical liquid chromatography in the enantiomers Daicel Chiralpak 5 250 mm x 50 200 detection dioxide 220 Example 139A enantiomer 5690 mg Rt chemical purity eic Daicel Chiralpak 5 250 mm x 3 detection dioxide 220 Rt 671 Example 140A 6080 mg Rt chemical purity eic Daicel Chiralpak 5 250 mm x dioxide of detection 3 Rt 671 Example 141A of ethyl dihydrochloride enantiomer 6080 mg of example ethyl carboxylate were mixed with 23 ml of a 4 N solution of hydrochloric acid in dioxane and stirred for 2 h at room temperature. The mixture was then concentrated to dryness. 6240 mg of the product was obtained, which was transformed without further characterization. Analogously to example 141 A The following Example 143A of ethyl enantiomer was prepared. 6240 mg of ethyl dichlorohydrate example 141 were suspended in 103 ml of mixed with my triethylamine and stirred for one hour at room temperature. The reaction solution was then mixed with ethyl acetate and mixed with ethyl acetate. The phases were separated and the aqueous phase was extracted once more with acetate. The combined organic phases were washed again with dried over sulphate, filtered and finally evaporated to 3600 mg 61 of the compound were obtained which were continued transforming without further characterization Analogously To Example 143A the following Example 145A of ethyl enantiomer was prepared. A solution of 200 mg of ethyl example in 3 ml of dry acetonitrile was mixed with 305 mg of methyl and 56 mg of anhydrous sodium carbonate and stirred for 4 hours at room temperature. in a microwave oven. The reaction solution was then cooled and purified dilineously by preparative HPLC. on 75 mg 29 of the compound of Rt 733 1 H NMR Analogously to Example 145A, the following Example 147A v Example 69A ethyl carboxyl ester enantiomer 1 was prepared and 25 g of ethyl racemic were separated by chiral phase supercritical liquid chromatography on the Daicel enantiomers. Chiralpak 5 250 mm x 50 dioxide of 400 detection 220 Example 147A 11 g Rt chemical purity of Daicel Chiralpak 5 250 mm x 1 detection 220 Example 69A enantiomer g Rt chemical purity of Daicel Chiralpak 5 250 mm x 1 detection 220 Example 148A v Example 74A of ethyl enantiomer 1 and 15 g of racemic ethyl carboxylate were separated by supercritical liquid chromatography in chiral phase in the Chiralpak enantiomers 20 400 mm x 50 400 detection dioxide 220 Example 148A enantiomer 5830 mg Rt chemical purity e Chiralpak 5 250 mm x dioxide of 3 detection 210 Example 74A enantiomer 6330 mg Rt chemical purity ee Chiralpak 5 250 mm x 3 detection dioxide 210 Example 149A methyl Gm of methyl bromide and g of methyl were dissolved in 160 ml of cooled to 0 and mixed The reaction mixture was then heated slowly to room temperature and stirred until the next day. After the reaction solution was cooled again to 0, it was mixed in portions with other g of sodium methoxide and After warming to room temperature, it was stirred again until the day. The reaction mixture was subsequently concentrated to dryness and the residue was purified by chromatography on ethyl silica gel. G 43 of the compound of 307 was obtained. Example 150A of methyl. of methyl in 150 ml of THF and 150 ml of ethanol with 427 mg of 10-palladium on carbon and stirred overnight at room temperature under a pressurized hydrogen atmosphere. The reaction mixture was then filtered and the resulting filtrate It was concentrated to obtain 93 g of the compound of Rt 309 1 H NMR Example 151A To a solution of g of methyl in 150 ml of dry THF was added. The mixture was slowly added dropwise at room temperature under an argon mi atmosphere of a 1M solution of lithium aluminum hydride. After the reaction mixture was continued stirring for one hour at room temperature, the reaction mixture was cooled to 0 ° C. The mixture was added slowly and cautiously with 150 ml of 1 M hydrochloric acid cooled. After the addition of acetate, the aqueous phase was separated and the organic phase was washed once with 1 M hydrochloric acid and once with saturated aqueous solution. The organic phase was then dried over sulfate, filtered and concentrated to. G 93 of the compound of Rt 263 1 H NMR was obtained. Example 152A To a solution of methanol in 100 ml of dichloromethane were slowly added dropwise to me. of thionyl chloride in 30 ml of After the end of the reaction mixture was heated to room temperature and continued stirring for two hours to this Then cooled again the reaction mixture to and slowly and cautiously was mixed under vigorous stirring with 100 ml of saturated aqueous sodium hydrogen carbonate solution until a pH value had been reached. After the phases were separated and the organic phase was dried over sulphate The mixture was filtered and concentrated to give 84 g of the compound of Rt. Example 153A of ethyl enantiomer. 1 g of ethyl, 746 mg of and 784 mg of potassium carbonate in 25 ml of acetonitrile were heated to and agitated until the next day. After filtering, the mixture of the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness in an evaporator. The residue obtained was purified by chromatography on silica gel ethyl acetate. Eleven mg of the compound was obtained. Rt 703 Example 154A of ethyl dihydrochloride enantiomer 1100 mg of example ethyl carboxylate were mixed with 12 ml of a 4 N solution of hydrochloric acid The mixture was then concentrated to dryness. 1045 mg of the product was obtained which was further processed without further characterization. Example 155A of ethyl enantiomer 1045 mg of ethyl carboxylate, dichlorhydrate, was suspended in 15 ml. The reaction solution was mixed with ethyl acetate and the phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed once again. with dried over sulfate were filtered and then concentrated to obtain 800 mg 86 of compound Rt 603 Ethyl enantiomer example 156A A solution of 208 mg of ethyl example in 3 ml of dry acetonitrile was mixed with 300 mg of methyl and 55 mg of anhydrous sodium carbonate and stirred for 4 h in a microwave oven. The solution was then cooled of reaction and purified directly by preparative HPLC acetonitrile water. mg 39 of the compound of Rt 765 Example 157A of ethyl. 2 g of ethyl 1433 mg of and 1507 mg of potassium carbonate in 50 ml of acetonitrile were added to and stirred until the next day after the mixture was filtered. The filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness in an evaporator. The obtained residue was purified by chromatography on silica gel ethyl acetate 2490 mg 95 of compound Rt 721 were obtained Example 158A of ethyl dihydrochloride 500 were mixed mg of ethyl carboxylate with my from a 4 N solution of hydrochloric acid in dioxane and stirred for 2 h at room temperature. The reaction mixture was then concentrated to 479 mg of the product which was further processed without further characterization was obtained. 479 mg of ethyl carboxylate dihydrochloride were suspended in me, mixed with my triethylamine and stirred for one hour at room temperature. the reaction solution with ethyl acetate and the phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed again with dried over sulphate, filtered and then concentrated to 383 mg 96. of compound Rt 621 Example 160A of ethyl A solution of 380 mg of ethyl carboxylate in 5 ml of dry acetonitrile was mixed with 533 mg of methyl and 97 mg of anhydrous sodium carbonate and stirred for 4 h in a microwave oven. The reaction solution was then cooled and purified directly by preparative HPLC. 178 mg 37 of the compound of Rt 783 were obtained. Examples of Example 1: Enantiomeric acid 752 mg of ethyl carboxylate 1 were suspended in 9 ml of THF and ml of water and they were mixed with 137 mg of hydroxide. The preparation was stirred until the next day after the reaction was complete, the THF was removed in a rotary evaporator and the The remaining mixture was diluted with water. The mixture was then acidified with acetic acid to a pH value and extracted several times with acetate. The combined organic phases were dried over sulphate, filtered and concentrated to 590 mg of the reference compound were obtained as Rt 1 634 1 H D NMR partially covered by the 1 c signal Example 2 Enantiomeric acid 735 mg Example ethyl carboxylate was suspended in 9 ml of THF and ml of water and mixed with 134 mg of hydroxide of The preparation was stirred until the next day after the reaction was complete, the THF was removed in a rotary evaporator and the remaining mixture was diluted with. Then it was acidified with acetic acid to a pH value and extracted several times with acetate. The combined organic phases were dried over sulfate were filtered and concentrated in. 617 mg 91 of the reference compound were obtained as foam Rt 634 1 Hd NMR partially covered by the signal From c Analogously to examples 1 and 2, the following were prepared. Example 12 Racemic acid 35 mg of ethyl in 1 ml of THF and 1 ml of water were suspended and mixed with 7 mg of hydroxide of the preparation. The following day after the THF was removed in a rotary evaporator and the remaining mixture was diluted with water. It was then acidified with 1 M hydrochloric acid and extracted several times with a mixture of ethyl acetate and the combined organic phases were dried on sulfate were filtered and concentrated to 29 mg content 81 of the reference compound were obtained as solid Rt 607 1 H DMSO d NMR partially covered by the signal of 11 1 Example 13: Enantiomeric acid 259 mg of ethyl acetate was suspended in Example 4. Mi was mixed with 2 ml of a 2 M solution of potassium hydroxide in water and stirred until the next day at temperature. After the mixture was completed, the mixture was slightly acidified. with my acetic acid and with 1 N hydrochloric acid and then concentrated to the The residue obtained was purified by HPLC. 183 mg 77 of the compound of Rt 607 1 H NMR covered with the signal were obtained. Analogously to Example 13, the following were prepared. Example 19: Enantiomeric acid 68 mg of ethyl carboxylate 1 were suspended in 4 ml. of THF and 2 ml of water and were mixed with 12 mg of hydroxide. The preparation was stirred until the next day after completion of the THF was removed in rotary evaporator and the remaining mixture was diluted with Then acidified with acid The combined organic phases were dried over sulfate, filtered and concentrated to give 33 mg 48 of Rt NMR compound of 1H DMSO d Example 20 Enantiomeric acid Suspended to a pH value and extracted several times with acetate. mg of example ethyl carboxylate in 4 ml of THF and 2 ml of water were added and mixed with 8 mg of hydroxide. The preparation was stirred until the next day after being mixed. Once the reaction was complete, the THF was removed on a rotary evaporator and the remaining mixture was diluted with water. It was then acidified with acetic acid to a pH value and extracted several times with acetate. The combined organic phases were dried over sulphate and filtered. They concentrated to 13 mg 32 of the compound of Rt NMR of d were obtained Analogously to example 20 the following were prepared Example 23 Enantiomeric acid 42 g of example ethyl carboxylate were dissolved in 429 ml of were mixed with 163 ml of sodium lye 1 N The reaction was then stirred overnight at the temperature. After the reaction had been completed, the dioxane was removed in a rotary evaporator and the remaining mixture was diluted with 750 ml of Then it was acidified with acetic acid to a pH value. The precipitated solid was filtered off with suction and washed several times with total water 250 ml of After the solid was suspended in 750 ml of water and stirred until the day After removing the filtrate again with suction, the solid was washed again with water and then dried overnight under high vacuum over phosphorus pentoxide as agent. The desiccant was then removed and the solid was dried for a further period of time. In this manner, 35 g 88 of the Rt-NMR compound of 1H dc were obtained Analogously to Example 20 and Example 23, the following were prepared Example 38: Enantiomeric acid: Example of ethyl acetate was suspended in 40 ml of dioxane and 20 ml of mixed with 658 mg of hydroxide and then stirred overnight at room temperature. After completion of the reaction, the dioxane was removed on a rotary evaporator and the remaining mixture was diluted with. Then it was acidified with acetic acid to a pH value. The precipitated solid It was removed by suction and washed several times with After the solid was absorbed in water and stirred at temperature After removing again by suction the solid was washed again with water and then dried until the next day under high vacuum a 95 g of the compound of 655 RMN of 1H dc were obtained Example 39 Nantiomeric acid G of ethyl example was dissolved in 50 ml of They were mixed with 21 ml of 1N sodium hydroxide solution and then stirred at the next temperature at the end of the reaction. After the dioxane was removed, the rotary evaporator was removed and the remaining mixture was diluted with. Then it was acidified with acetic acid to a pH value. The precipitated solid was separated by filtration, washed several times with water and then dried overnight on the following day. 94 g of Rt NMR compound of 1H dc were obtained Example 40 Ethyl nantiomeric acid Example in 50 ml of mixed with my 1 N sodium hydroxide solution and stirred overnight at room temperature. Then, another 1 ml of 1 M sodium hydroxide solution was added and the mixture was continued stirring for two hours. After the completion, the dioxane was removed in a rotary evaporator and the remaining mixture was diluted with A Then it was acidified with acetic acid to a pH value. The precipitated solid was filtered off, washed several times with water and then dried for three days in a vacuum drying cabinet at 40 ° C. 673 mg 94 of the Rt compound were obtained. 673 NMR of 1H dc Analogously to Example 40 the following were prepared Example 43 Nantiomeric acid 75 mg of ethyl were dissolved Example in 2 ml of were mixed with my 1N sodium hydroxide solution and stirred until the next day at temperature After having After completion of the reaction, the dioxane was removed on a rotary evaporator and the remaining mixture was diluted with. Then, it was acidified with acetic acid to a pH value. The precipitated solid was filtered off, washed several times with water and then dried for three days. in a vacuum drying cabinet at 40 58 mg 78 of the compound of Rt 691 1 H DMSO NMR were obtained Example 44 Acid Enantiomer 98 mg of ca. Ethyl rboxylate Example in my was mixed with 1N sodium hydroxide solution and then stirred overnight at the temperature. After the reaction was complete, the dioxane was removed in a rotary evaporator and the remaining mixture was diluted with. Then it was acidified with acetic acid at a pH value The precipitated solid was removed by being washed several times with water and then dried for three days in a vacuum drying cabinet at 40. 71 mg of the 723 nmr compound of 1H d were obtained. Example 45 Racemic acid 173 mg of ethyl were dissolved in 4 ml of mixed with 1 N sodium hydroxide solution and then stirred at the next temperature. After the reaction was complete, the dioxane was removed in a rotary evaporator and the remaining mixture was evaporated. It was then diluted with acetic acid to a pH value. The precipitated solid was filtered off with washing several times with water and then is dried for three days in the vacuum dryer a 134 mg of the compound of Rt 1 741 1 H NMR were obtained d Evaluation of pharmacological efficacy The pharmacological effect of the compounds of the invention can be demonstrated in the following Stimulation of soluble guanylate cyclase Recombinant in vitro Studies for the stimulation of recombinant soluble guanylate cyclase by means of the compounds of the invention with and without sodium nitroprusside as well as with and without the GCs-dependent inhibitor are carried out according to the procedure described in detail in next quote Gerzer and soluble guanilyl cyclase expressed in a Stimulation by nitric oxide and carbon Guanylate cyclase is obtained without the heme group by adding Tween 20 to the assay buffer in the concentration The activation of the GCs by a test substance is indicated as stimulation of x times of the activity The result of Example 2 is shown in the Table on d Example 23 in Table 1B and that of Example 39 in Table Table Stimulation of recombinant soluble guanylate cyclase in vitro by Example 2 Table Stimulation of recombinant soluble guanylate cyclase in vitro by example 23 Table Stimulation of recombinant soluble guanylate cyclase in vitro by Example 39 ODQ In Tables 1B and 1C it can be seen that a stimulation of both the enzyme with heme as well as the free enzyme of the combination of Example Example 23 and Example 39 respectively with a donor having no effect is achieved is that the action is not enhanced as could be expected in the case of a GC activator acting by means of a mechanism that depends on the group the effect of the activator GCs of the invention is not blocked by an inhibitor of the soluble guanylate cyclase dependent on but instead it is even The results in Tables 1B and so prove the mechanism of action of the compounds of the invention as activators of guanylate cyclase Effect on a cell line indicative of recombinant quilamylate cyclase The cellular action of the compounds according to the invention is determined on a cell line indicative of recombinant guanylate cyclase as described in Wunder et. The representative values for the compounds of the invention are shown in the Table Table activating effect of GCs in the cell CHO reporter in vitro minimum concentration Vascular relaxation effect in vitro Rabbits are sacrificed by an intravenous injection of sodium thiopental 50 and the Arteria Saphena is removed and cut into 3 mm rings. The rings are individually mounted each in a pair of open shaped hooks on the ends made of a special wire of mm Each ring is placed pretensioned in 5 ml of organ bath with warm Henseleit solution at 37 gasified with the following NaCl 119 KCI x 2 1 x 7 H20 KH2PO4 25 glucose 10 bovine serum albumin The force of contraction is captured with cells Statham is quantified and digitized by trans trainers as well as recorded in parallel writing equipment Contractions are induced by the addition of After several general control cycles the substance to be analyzed is added in increasing doses in each subsequent pass and the intensity of the contraction achieved under the influence is compared of the test substance with the intensity of the contraction achieved in the last pass. From here the concentration that is necessary to reduce to 50 the contraction achieved in the previous control is calculated. The standard application volume amounts to 5 The proportion of DMSO in the bath solution is equivalent to Representative results of the compounds according to the invention are indicated in the Table Table Effect of vascular relaxation in vitro Bronchodilator effect in vitro and in vivo Broncorrelation in vitro Bronchial rings of mouse or guinea pig are removed and prepared and individually assemble each one in a couple of hooks openly in the ends made of a special wire of mm of Each ring is placed pretensioned in 5 ml of organ bath with lukewarm solution to 37 gasified with bronchial rings are previously contracted with metalcoline to then study the broncorrelaxation by adding increasing concentrations 9 to 106 of the test substance The results are evaluated as percentage relaxation in relation to the preconstriction produced by the Evaluation in animal tests to study the effect of bronchoconstriction in the asthma model All animals are treated before starting the test provocation with an esophageal or shaped probe In this way the animals of the treatment groups received the substance from the control animals received a corresponding solution After the phase of anesthesia was passed to the animals and after the placement of an esophageal catheter and reach a steady state of the first lu The pulmonary function is measured before the measurement. The measurement parameters are, among others, pulmonary resistance and dynamic compliance as well as respiration volume and respiratory rate. Data storage and statistical evaluation is carried out with computer programs specially developed for These pulmonary function tests are carried out a definite inhalative exposure of test animals to aerosolized methacholine from an asthma-induced bronchoconstriction in a manner not During and 3 minutes after exposure is continued with the recording of the operating parameters The concentration and the dose of MCh in the inhalation air are controlled and monitored by a system of self-regulation of dose measurement of the aerosol concentration and of the volume by When the dose is reached it is terminated by increasing the resistance and in comparison with the positive control with treatment determines the inhibitory effect of the Study substances in the model of asthma All animals except for those with allergen control ovalbumin and adjuvant are sensitized to the control group instead of physiological saline. All groups are then challenged with 6 treatment groups are used in the study test substances in 3 dose groups in addition a reference group treated by route with a negative control group with treatment and apparent provocation and a positive control group elicited with treatment protocol and from day 14 and 21 was used. sensitizes all animals with ovalbumin and adjuvant via the negative control receives treatment with On day 28 and 29 the provocation of the animals is performed with an intratracheal administration of a solution of The test substances are administered intragastrally or inhalatively 1 h before each provocation with the allergen by way A reference group receives treatment with dexamethasone by 18 h and 1 h before each intratracheal challenge with the positive and negative control groups are treated correspondingly with the airway hyperresponsiveness response In the first study in the animals the hyperreactivity of the respiratory tract with respect to stimuli no For h After ovalbumin challenge, a hyperreactivity test is performed in the form of an increased inhalational provocation of methacholine. The patient is anesthetized with orotracheal intubation and pulmonary function is measured before the provocation by body plethysmography parameters such as frequency, dynamic compliance and resistance. After the measurements are completed, the dose effectiveness curve for each animal is elaborated and the hyperreactivity of the positive control is evaluated with respect to the negative control or its respective inhibition in the groups. After the animals were sacrificed, samples were taken from gre and a pulmonary lavage was performed From the lavage fluid the total amount of cells and the differential cell image including the amount of eosinophils in the remaining amounts of BAL fluid are determined first. After or eventually on another occasion can be determined other parameters The lung tissue is reserved for a histopathological study Heart with isolated perfusion according to Lanqendorff They are anesthetized with male Wistar rats with a body weight of After opening the preparation is cut and connected by cannulas through the aorta to a team retrograde perfusion of the heart with a buffer solution of 95 O2 and 5 pH composition in NaC1 KCI NaHCOs glucose pyruvate sodium with 9 flow To register the force of contraction of the heart a balloon is inserted through an opening in the left atrium made of thin plastic filled with water and fixed to a tube in the ventricle The balloon is connected with a final diastolic pressure recording device is adjusted to mmHg by the volume of the perfusion pressure is detected by a second recording device The data are sent and recorded through a bridge reinforcement to a After 40 min of time of the respective test substance is added with a final concentration of the perfusion solution during 20 which produces a reduction of the perfusion pressure as a sign of the dilation After perfusion of the hearts is performed for another 120 minutes without substance In order to determine the reversibility of the perfusion pressure drop, the perfusion pressure value is plotted after 60 min of the wash phase in relation to the maximum decrease in perfusion pressure caused by the perfusion substance. and in form The index thus obtained is evaluated as a measure of the residence time of the test substance in the place of Hemodynamics in anesthetized pigs Góttinger Ellegaard minicerdos of kg of both The animals were sedated by the administration of 25 ketamine and 10 The induction of anesthesia was carried out by administration of 2 of ketamine and of To maintain the anesthesia was applied via ketamine and midazolam infusion as well as 150 of pancuronium bromide After intubation the animals were ventilated artificially using a respirator with constant breathing volume my Viasys or GE Engstrom so that an endothelial concentration of CO2 of 5 was achieved Ventilation was carried out with air enriched with 40 oxygen and it is adjusted in such a way that a final expiration pressure of 5 cm of column is achieved. For the measurement of parameters such as blood pressure and heart rate pressure, catheters are placed in the carotid for the measurement of blood pressure and a catheter through the jugularis in the artery Hemodynamic signals are recorded and evaluated by recorders pressure amplifiers and as logging software After the instrumentation is finished and for the purpose of increasing the pressure a permanent infusion with a thromboxane analog is initiated Infusion of F2a or Cayman Chemical dissolved in saline for the purpose of achieve an increase in the mean pressure to values above 25 After 30 minutes of initiation of the infusion, a stabilization is produced and the test substances are administered by infusion via or through the preparation of the inhalation solution. Next, to prepare the stock solution for an animal of 4 kg, 1 mg of the test compound is weighed and dissolved in 3 ml of total volume 99 of citric acid solution to 1 N sodium hydroxide solution to adjust the pH value to the solution then it is diluted with citric acid to which previously it was adjusted with sodium hydroxide solution to a pH value until reaching the concentration In each for each animal of 4 kg are sprayed 3 ml of the test compound solution by means of the nebulization system Pro in the branch of the inhalation tube of the circuit The mean time of nebulization is 7 minutes after the initiation of the inhalation administration of the activators of GCs animal models with HPA The tests were performed in Gotttinger minicerdos in anesthetized rats or in awake dogs instrumented by pulmonary hypertension is induced by infusion of a thromboxane analog by acute hypoxia treatment or by several weeks by administration of the nebulization of the substances The test is carried out using a nebulization system or by means of powder solution application devices for the experimental intratracheal application Dry Powder Century or after the nebulization of solids that are connected to the branch of the tube of inspiration of the substance. in relation to molecular structure as solids or signals hemodynamics are recorded and evaluated by means of pressure recording devices intensifiers Germany or CardioMEMS and / or logging software After prolonged tests on rats with an evaluation can also be made Radiotelemetric measurement of blood pressure and heart rate in awake rats The measurements described below made in awake rats are used a telemetric system of the company Data Sciences International that can be obtained in the The system consists of 3 components 1 implant transmitter transmitters of receivers connected by means of a Data Exchange multiplier with a computer The telemetry equipment allows continuous recording of blood pressure and heart rate in animals awake in their environment. The studies were performed on adult female Wistar rats with a body weight. The test animals after implantation of the transmitter s They keep individually in cages Makrolon type They have free access to standard food and The rhythm in the test laboratory is alternated by environmental lighting at morning and at the implant. The telemetric transmitters used are surgically implanted in aseptic conditions to the test animals at least 14 days before the first animal is made. thus instrumented they can be used repeatedly after having healed the wound and the incorporation of For the implant the animals are anesthetized fasting with pentobarbital 50 are shaved in the abdomen and se After opening the abdominal cavity along the linea alba is placed The catheter measuring the system above the bifurcation towards the cranial in the descending Aorta is fixed with tissue adhesive. The transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed. After the surgery a antibiotic 10 60 g of weight to prevent as well as an analgesic 4 Substances v Unless described The substances to be analyzed are administered orally to a group of animals, respectively, by means of a probe. According to an application volume of 5 body weight, the test substances are dissolved in suitable solvent mixtures or suspended in 5% aliphatic. control is used a group of animals treated with Development of the telemetric measurement system is configured to 24 Each test is recorded under a number of A instrumented rats included in the system was respectively assigned an antenna own reception Implanted transmitters can be activated from the outside by means of an installed magnetic switch and they are switched to emit during the realization of the emitted signals can be registered online through a data acquisition system for and to be processed. The data file is made respectively in a file created for that purpose that is identified with the number of In the standard development is measured cad time for 10 1 systolic blood pressure diastolic blood pressure average blood pressure and heart rate The recording of the measured values is repeated by computerized control in intervals of 5 The source data collected as absolute value is corrected in the diagram with the barometric pressure currently measured Pressure Reference and are filed as data Other documents are indicated in the documentation of the manufacturing company Unless it has been described that the administration of the test substances is carried out on the day of the test at the After the administration the parameters described above are measured During the 24 After the end of the test, the individual data collected by the analysis software are classified. As a blank value, the moment of 2 hours before the application is set so that the selected data set includes the period of the hours of the rehearsal day until daylight hours Data are equated du For a pre-settable time by determining the average value of 15 and transferring them as a text file to a support of the pre-sorted and compressed measurement values are transferred to the Excel forms and are represented in the form The data file collected is performed for each test day in an individual file identified with the number of results and the test protocols are classified on paper by numbers and are archived in Ertl and Experimental heart failure in cardiovascular effects on circadian rhythms and on myocardlal adrenergic Verification of the potential for desaturation of substances of Gotttinger Ellegaard minicerdos of kg of both The animals were sedated by the administration of ketamine and 10 of The induction of anesthesia was carried out by administration of 2 ketamine and for the maintenance of anesthesia was applied via ketamine and infusion midazolam as well or 150 of pancuronium bromide After the intubation the animals artificially using a respirator with constant breathing volume 30 Viasys or GE Engstrom so that an endothelial CO2 concentration of 5 is achieved. The ventilation was carried out with the air enriched with oxygen 40 and is adjusted in such a way that pressure is achieved end of expiration of 5 cm column For the measurement of parameters such as blood pressure pressure and heart rate catheters are placed in the carotis for the measurement of blood pressure and a catheter through the jugularis in the artery The hemodynamic signals are recorded and evaluated by pressure recorders amplifiers and as recording software. A 4 French oximetry catheter is placed in the left femoral artery and connected to a surveillance monitor in order to measure arterial oxygen saturation. continuous all the parameters for the evaluation are calculated the average values of stable intervals of at least 1 min values maximum increase of 3 min conditions Profile pHOx plus Nova blood gases are determined 3 min after the start of each bronchial occlusion cycle Individual pulmonary ventilation is achieved on the side when the tracheal tube is advanced inside the The right main bronchus and the left side of the lung closed to the ventilation by inflating a The placement of the tube is confirmed by In each animal several cycles of individual ventilation are performed for 10 min of interrupted respectively for 30 minutes of ventilation The first cycles are They are used as control cycles to guarantee the reproducibility of the following The influence of solvents and the test substance dissolved in them after intravenous administration is measured with respect to the following parameters arterial pressure arterial oxygen saturation and pressure The objective of the use of the animal model is to identify a substance that causes the greater possible reduction in PAP or the increase in PAP caused by hypoxia without an increase in oxygen desaturation due to dilatation of pulmonary arteries in non-ventilated lung areas. Becker et bei sekundárer pulmonarer Hypertonie Riociguatim Pneumologie 65 Exemplary embodiments for pharmaceutical compositions The compounds according to the invention can be transformed in the following manner into preparations 100 mg of the compound according to 50 mg of lactose 50 mg of corn starch 10 mg of polyvinylpyrrolidone and 2 mg of stearate of Weight of the tablet 212 diameter 8 radius of curvature 12 The mixture of the compound according to the lactose and starch is granulated with a 5% solution of PVP in the granules are dried and mixed with the magnesium stearate for 5 hours. This mixture is pressed with a conventional compression press the compressed format see the guide value used for compression is a pressing force of 15 Suspension for administration 1000 mg of the compound according to 1000 mg of ethanol 400 mg of xanthan EE and 99 g of A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of suspension Rhodigel is suspended in the compound according to the invention is added to the water is added while the mixture is stirred for hours until the expansion of the solution is completed for administration 500 mg of the compound according to the g of polysorbate and 97 g of polyethylene glycol A single dose of 100 mg of the compound according to the invention corresponds to 20 g of solution The compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate while the stirring operation continues until the dissolution is complete of the compound according to the Solution The compound according to the invention is dissolved at a concentration below the solubil saturation ad in a physiologically acceptable solvent saline solution of glucose to solution of PEG 400 to 30 The solution is sterilized by filtration and filled into sterile injectable containers free of insufficient OCRQuality

Claims (12)

  1. CLAIMS A compound of the formula (I) characterized because R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, Y A represents a group of the formula in which * indicates the respective binding point with the rest of the molecule, L2 represents straight chain (C1-C6) alkanediyl, L3 represents a bond, -O-, -CH2-, -CH2-CH2- or -CH = CH-, R2 represents (C1-C4) alkyl, which may be substituted up to six times with fluorine, or represents (C3-C6) cycloalkyl, which may be mono- or di-substituted, in the same or different manner, with a moiety selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl and (C1-C4) alkyl, or represents a 4- to 6-membered heterocylil containing one or two identical or different heteroanal members selected from the group consisting of N (R4), O, S and S (O) 2 wherein R4 represents (C1-C4) alkyl or (C1-C4) alkylcarbonyl or in the case where N (R4) represents an annular nitrogen atom by means of which said heterocyclyl is bonded to the adjacent phenyl group, is not present, or represents a 5-membered heteroaryl containing one, two or three identical or different ring heteroatoms selected from the group consisting of N, O and S and optionally may be fused with a phenyl ring, the heteroaryl ring and the optionally condensed phenyl ring being mono- or di-substituted, respectively, in the same or different manner with a radical selected from the group consisting of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, (C1-C4) alkyl, difluoromethoxy, trifluoromethoxy and (C 1 -C 4) alkoxy, or represents chlorine, Y R3A, R3B, R3C and R3D independently represent hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C1-C4) alkyl, difluoromethyl, trifluoromethyl, (C1-C4) alkoxy, difluoromethoxy and trifluoromethoxy , as well as its salts, solvates and the solvates of the salts.
  2. 2. The compound of the formula (I) according to claim 1, characterized in that R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, Y A represents a group of the formula , in which * indicates the respective binding point with the rest of the molecule, L2 represents straight chain (C3-C5) alkanediyl, L3 represents a bond, -CH2-CH2- or -CH = CH-, R2 represents (C1-C4) alkyl, which may be trisubstituted with fluorine, or represents cyclopentyl or cyclohexyl, which may be mono- or di-substituted, in the same or different manner, with a moiety selected from the group consisting of fluorine, methyl and trifluoromethyl, or represents a 5- or 6-membered heterocyclyl of the formula in which ** indicates the respective point of attachment with the adjacent phenyl group and R4 represents methyl, acetyl or propionyl, or represents 5-membered heteroaryl selected from the group consisting of 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,4-oxadiazolyl, 1,3,4-oxadiazolyl 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl, the aforementioned heteroaryl groups being able to be substituted respectively with methyl or trifluoromethyl Y wherein 1, 2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl and 1,3-thiazolyl can be fused with a phenyl ring, which in turn can be substituted with fluorine, chlorine, cyano, methyl, trifluoromethyl or trifluoromethoxy , R3A represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl, R3B represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy, R3C represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl, Y R3D represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy, as well as its salts, solvates and the solvates of the salts.
  3. 3. The compound of the formula (I) according to claim 1 or 2, wherein R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, Y A represents a group of the formula in which * indicates the respective binding point with the rest of the molecule, L2 represents straight chain (C3-C5) alkanediyl, L3 represents a bond, -CH2-CH2- or -CH = CH-, R2 represents (C1-C4) alkyl, which may be trisubstituted with fluorine, or represents cyclopentyl or cyclohexyl, which may be mono- or di-substituted, in the same or different manner, with a moiety selected from the group consisting of fluorine, methyl and trifluoromethyl, or ** represents 6-membered heterocyclyl of the formula R4 wherein ** indicates the point of attachment with the adjacent phenyl group Y R4 represents methyl, acetyl or propionyl, or represents 1,3-benzoxazol-2-yl, 1,2-benzoxazol-3-yl or 1,3-benzothiazol-2-yl which may be substituted with a moiety selected from the group consisting of fluoro, chloro, cyano, methyl , trifluoromethyl and trifluoromethoxy, R3A represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl, R3B represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy, R3C represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl, Y R3D represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl or trifluoromethoxy, as well as its salts, solvates and the solvates of the salts.
  4. 4. The compound of the formula (I) according to claim 1, 2 or 3, characterized in that R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, Y A represents a group of the formula in which * indicates the respective binding point with the rest of the molecule, L3 represents a bond or -CH2-CH2-, R2 represents tert-butyl, cyclohexyl, 4- (trifluoromethyl) cyclohexyl or 1,3-benzoxazol-2-yl, which may be substituted with chloro, cyano, methyl or trifluoromethyl, R3C represents hydrogen or chlorine, Y R3D represents hydrogen, fluorine or trifluoromethyl, as well as its salts, solvates and the solvates of the salts.
  5. 5. A process for the preparation of a compound of the formula (I), as claimed in claims 1 to 4, characterized in that: [A] a compound of the formula (II) is reacted wherein R1 and L1 have the meanings indicated in claims 1 to 4 Y T and T2 are the same or different and represent (C1-C4) alkyl, in the presence of a base with a compound of the formula (III) wherein A has the meanings indicated in claims 1 to 4 and X1 represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, or [B] a compound of the formula (IV) is reacted wherein R1 and A have the meanings indicated in claims 1 to and T2 represents (C1-C4) alkyl, in the presence of a base with a compound of the formula (V) (V) wherein L1 has the meanings indicated in claims 1 to 4, T1 represents (C1-C4) alkyl, Y X2 represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, and the resulting compound in each case of the formula (VI) (SAW) wherein R1, A, L1, T1 and T2 have the meanings indicated above, then is transformed by hydrolysis of the ester groups -C (O) 0T1 and -C (O) 0T2 into the corresponding dicarboxylic acid of the formula (I) and optionally the compounds of formula (I) thus obtained are separated into their enantiomers and / or diastereomers and / or optionally are transformed with the corresponding (i) solvents and / or (i) bases in their solvates, salts and / or solvates of the salts.
  6. 6. The compound as claimed in any one of claims 1 to 4, for the treatment and / or prevention of diseases.
  7. 7. The compound as claimed in claims 1 to 4, for use in a method for the treatment and / or prevention of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, thromboembolic diseases, ischemias , vascular diseases, microcirculatory disorders, renal failure, fibrotic diseases and arteriosclerosis.
  8. 8. The use of a compound as claimed in any of claims 1 to 4, for the preparation of a medicament for the treatment and / or prevention of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, thromboembolic diseases, ischemia, vascular diseases, microcirculatory disorders, renal failure, fibrotic diseases and arteriosclerosis.
  9. 9. A medicament, characterized in that it comprises a compound as claimed in any of claims 1 to 4, in combination with one or more inert, non-toxic adjuvants suitable for pharmaceutical use.
  10. 10. A medicament characterized in that they contain a compound as recited in any one of claims 1 to 4 in combination with one or more other active ingredients selected from the group consisting of organic nitrates, NO donors, PDE5 inhibitors, prostacyclin analogues, IP receptor agonists, endothelin receptor antagonists, guanylate cyclase stimulators, tyrosine kinase inhibitors, anti-obstructive agents, anti-inflammatory and / or immunosuppressive agents, antithrombotic agents, hypotensive agents and lipid metabolism modifiers.
  11. 11. The medicament according to claim 9 or 10 for the treatment and / or prevention of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, thromboembolic diseases, ischemia, vascular diseases, microcirculatory disorders, renal insufficiency , fibrotic diseases and arteriosclerosis.
  12. 12. A method for the treatment and / or prevention of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, thromboembolic diseases, ischemia, vascular diseases, microcirculatory disorders, renal insufficiency, fibrotic diseases and arteriosclerosis in humans and animals by administering an effective amount of at least one compound as claimed in any one of claims 1 to 4 or of a medicament as claimed in any of claims 9 to 11.
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